Abstract
The role of melatonin as a neurotransmitter, a hormone, and a possible therapeutic agent has been a matter of controversy (Brainard 1978; Reiter 1991; Hajak et al. 1996; Huether 1996; Jansen et al. 2006) ever since melatonin was isolated and identified as N-acetyl-5-methoxytryptamine by Lerner et al. (1958) and characterized by Axelrod and Wurtman (1966). Melatonin is synthesized and released by the pineal gland and has been shown to play a key role in the regulation of mammalian circadian rhythms and reproductive functions (Reiter 1991; Arendt et al. 1995; DiBella and Gualano 2006). Melatonin is also produced in extrapineal sites, such as the retina (Lundmark et al. 2006), the Harderian glands, and the gut (Huether 1993, 1994; Messner et al. 2001). It should however be noted that methods for the identification of peptides and neurotransmitters have reached extremely high levels of sensitivity; as a consequence, their presence in a tissue does not necessarily indicate that a relevant physiological function is subserved in that organ or tissue. Melatonin is synthesized from 5-hydroxytryptamine (5-HT) by a two-step biochemical pathway (Reiter 1991). Initially, 5-HT is acetylated to produce N-acetylserotonin, which is subsequently O-methylated to form melatonin.
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References
Other Peptide Hormones
Arendt J, Deacon S, English J, Hampton S, Morgan L (1995) Melatonin and adjustment to phase shift. J Sleep Res 4:74–79
Axelrod J, Wurtman RJ (1966) The formation, metabolism and some actions of melatonin, a pineal gland substance. Res Publ Assoc Res Nerv Ment Dis 43:200–211
Brainard GC (1978) Pineal research: the decade of transformation. J Neural Transm Suppl 3–10
DiBella L, Gualano L (2006) Key aspects of melatonin physiology: thirty years of research. Neuro Endocrinol Lett 27(4):425–432
Hajak G, Rodenbeck A, Hardeland R, Hüther G (1996) Melatonin: Vom Stiefkind der Hormonforschung zur Goldmarie der Vermarktungsstrategen. TW Neurologie Psychiatrie 10:384–390
Huether G (1993) The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia 49:665–670
Huether G (1994) Melatonin synthesis in the gastrointestinal tract and the impact of nutritional factors on circulating melatonin. Ann N Y Acad Sci 719:146–158
Huether G (1996) Melatonin as an antiaging drug: between facts and fantasy. Gerontology 42:87–96
Jansen SL, Forbes DA, Duncan V, Morgan DG (2006) Melatonin for cognitive impairment [review]. Cochrane Database Syst Rev CD003802
Lerner AB, Case JD, Takahashi Y, Lee Y, Mori W (1958) Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc 81:2587
Lundmark PO, Pandi-Perumal SR, Srinivasan V, Cardinali DP (2006) Role of melatonin in the eye and ocular dysfunctions. Vis Neurosci 23(6):853–862
Messner M, Huether G, Lorf T, Ramadori G, Schwörer H (2001) Presence of melatonin in the human hepatobiliary-gastrointestinal tract. Life Sci 69:543–551
Reiter RJ (1991) Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 12:151–180
Melatonin Receptor Binding
Audinot V, Mailliet F, Lahaye-Brasseur C, Bonnaud A, Le Gall A, Amossé C, Dromaint S, Rodriguez M, Nagel N, Galizzi JP, Malpaux B, Guillaumet G, Lesieur D, Lefoulon F, Renard P, Delagrange P, Boutin JA (2003) New selective ligands of human cloned MT1 and MT2 receptors. Naunyn-Schmiedebergs Arch Pharmacol 367:553–561
Browning C, Beresford I, Fraser N, Giles H (2000) Pharmacological characterization of human recombinant mt1 and MT2 receptors. Br J Pharmacol 129:877–886
Charton I, Mamai A, Bennejean C, Renard P, Delagrange P, Morgan PJ, Howell HE, Gourdel-Martin ME, Viaud MC, Guillaumet G (2000a) Synthesis and biological activity of new melatonin receptor ligands. Pharm Pharmacol Commun 6:49–60
Charton I, Mamai A, Bennejean C, Renard P, Howell HE, Guardiola-Lamaître B, Delagrange P, Morgan PJ, Viaud MC, Guillaumet G (2000b) Substituted oxygenated heterocycles and thio-analogues: synthesis and biological evaluation as melatonin ligands. Bioorg Med Chem 8:105–114
Depreux P, Lesieur D, Mansour HA, Morgan P, Howell HE, Renard P, Caignard DH, Pfeiffer B, Delagrange P, Guardiola B, Yous S, Demarque A, Adam G, Andrieux J (1994) Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J Med Chem 37:3231–3239
Dubocovich ML, DelPedro A, Masana MI (1997a) The efficacy of melatonin receptor analogues is dependent on the level of human melatonin receptor subtype expression. Chronobiol Int 14:45
Dubocovich ML, Masana MI, Iacob S, Sauri DM (1997b) Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn-Schmiedebergs Arch Pharmacol 355:365–375
Dubocovich ML, Cardinali DP, Delagrange P, Krause DN, Strosberg D, Sugden D, Yocca FD (2001) Melatonin receptors. The IUPHAR compendium of receptor characterization and classification. IUPHAR Media, London, pp 270–277
Middleton B (2006) Measurement of melatonin and 6-sulphatoxymelatonin. Methods Mol Biol 324:235–254
Nonno R, Lucini V, Spadoni G, Pannacci M, Croce A, Esposti D, Balsamini C, Tarzia G, Fraschini F, Stankow BM (2000) A new melatonin receptor ligand with mt1-agonist and MT2-antagonist properties. J Pineal Res 29:234–240
Nosjean O, Ferro M, Cogé F, Beauverger P, Henlin JM, Lefoulon F, Fauchère JL, Delagrange P, Canet E, Boutin JA (2000) Identification of the melatonin binding site MT 3 as the quinone reductase 2. J Biol Chem 275:31311–31317
Nosjean O, Nicolas JP, Klupsch F, Delagrange P, Canet E, Boutin JA (2001) Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2. Biochem Pharmacol 61:1369–1379
Reppert SM, Waever DR, Ebisawa T (1994) Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13:1177–1185
Reppert SM, Godson C, Mahle CD, Waever DR, Slaugenhaupt SA, Gusella JF (1995) Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A 92:8734–8738
Zlotos DP (2005) Recent advances in melatonin receptor ligands. Arch Pharmacol (Weinheim) 338(5–6):229–247
In Vitro Assay of Melatonin: Inhibition of Forskolin-Stimulated cAMP Accumulation
Barrett P, MacDonald A, Helliwell R, Davidson G, Morgan P (1994) Cloning and expression of a new member of the melanocyte-stimulating hormone receptor family. J Mol Endocrinol 12:203–213
Browning C, Beresford I, Fraser N, Giles H (2000) Pharmacological characterization of human recombinant mt1 and MT2 receptors. Br J Pharmacol 129:877–886
Charton I, Mamai A, Bennejean C, Renard P, Delagrange P, Morgan PJ, Howell HE, Gourdel-Martin ME, Viaud MC, Guillaumet G (2000a) Synthesis and biological activity of new melatonin receptor ligands. Pharm Pharmacol Commun 6:49–60
Charton I, Mamai A, Bennejean C, Renard P, Howell HE, Guardiola-Lamaître B, Delagrange P, Morgan PJ, Viaud MC, Guillaumet G (2000b) Substituted oxygenated heterocycles and thio-analogues: synthesis and biological evaluation as melatonin ligands. Bioorg Med Chem 8:105–114
Conway S, Canning SH, Howell HE, Mowat ES, Barrett P, Drew JE, Delagrange P, Lesieur D, Morgan PJ (2000) Characterization of human melatonin mt1 and MT2 receptors by CRE-luciferase reporter assay. Eur J Pharmacol 390:15–24
Ebisawa T, Karne S, Lerner MR, Reppert SM (1994) Expression cloning of a high-affinity melatonin receptor from Xenopus dermal melanophores. Proc Natl Acad Sci U S A 91:6133–6137
Morgan PJ, Lawson W, Davidson G, Howell HE (1989) Melatonin inhibits cyclic AMP production in cultures ovine pars tuberalis cells. J Mol Endocrinol 3:R5–R8
Reppert SM, Godson C, Mahle CD, Waever DR, Slaugenhaupt SA, Gusella JF (1995) Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A 92:8734–8738
Dopamine Release from Rabbit Retina
Dubocovich ML (1985) Characterization of a retinal melatonin receptor. J Pharmacol Exp Ther 234:395–401
Dubocovich ML, Masana MI, Iacob S, Sauri DM (1997) Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn-Schmiedebergs Arch Pharmacol 355:365–375
Effect on Xenopus Melanophores
Danilolos A, Lerner AB, Lerner MR (1990) Action of light on frog pigment cells in culture. Pigment Cell Res 3:38–43
TeckTeh M, Sugden D (1998) Comparison of the structure-activity relationships of melatonin receptor agonists and antagonists: lengthening the N-acyl side-chain has differing effects on potency on Xenopus melanophores. Naunyn-Schmiedebergs Arch Pharmacol 358:522–528
Vasoconstrictor Activity of Melatonin
Black JW, Leff P, Shankley NP (1985) An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation. Br J Pharmacol 84:561–571
Delagrange P, Ting KN, Kopp C, Lahaye C, Lesieur D, Weibel L, Bennejean C, Renard R, Retton MC (1999) In vitro and in vivo antagonist properties of S 22153, a new melatonin ligand. Fundam Clin Pharmacol 13:253
Evans BK, Mason R, Wilson VG (1992) Evidence for direct vasoconstriction activity of melatonin in ‘pressurized’ segments of isolated caudal artery from juvenile rats. Naunyn-Schmiedebergs Arch Pharmacol 346:362–365
Halpern W, Osol G, Coy GS (1984) Mechanical behavior of pressurized in vitro prearteriolar vessels determined with a video system. Ann Biochem Eng 12:463–479
Ting KN, Dunn WR, Davies DJ, Sugden D, Delagrange P, Guardiola-Lamaître B, Scalbert E, Wilson VG (1997) Studies on the vasoconstrictor action of melatonin and putative melatonin receptor ligands in the tail artery of juvenile Wistar rats. Br J Pharmacol 122:1299–1306
Viswatanan M, Scalbert DP, Guardiola-Lamaître B, Saavedra JM (1997) Melatonin receptors mediate contraction of rat cerebral artery. NeuroReport 8:3847–3849
Melatonin’s Effect on Firing Rate of Suprachiasmatic Nucleus Cells
Liu C, Weaver DR, Jin X, Sherman LP, Pieschl RL, Gribkoff VR, Reppert SM (1997) Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19:91–102
Meijer JH, Reitveld WJ (1989) Neurophysiology of the suprachiasmatic circadian pacemaker in rodents. Physiol Rev 69:671–707
Moore RY (1983) Organization and function of a central nervous system circadian oscillator: the suprachiasmatic nucleus. Fed Proc 42:2783
Ying SW, Zhang DX, Rusak B (1993) Effect of serotonin agonists and melatonin on photic responses of hamster geniculate leaflet neurons. Brain Res 628:8–16
Ying SW, Rusak B, Delagrange P, Mocaër E, Renard P, Guardiola-Lamaître B (1996) Melatonin analogues as agonists and antagonists in the circadian system and other brain areas. Eur J Pharmacol 296:33–46
Zhang DX, Rusak B (1989) Photic sensitivity of geniculate neurons that project to the suprachiasmatic nuclei of the contralateral geniculate. Brain Res 504:161–164
Melatonin’s Effect on Circadian Rhythm
Benloucif S, Dubocovich ML (1996) Melatonin and light induce phase shifts of circadian rhythms in the C3H/HeN mouse. J Biol Rhythms 11:113–125
Delagrange P, Ting KN, Kopp C, Lahaye C, Lesieur D, Weibel L, Bennejean C, Renard R, Retton MC (1999) In vitro and in vivo antagonist properties of S 22153, a new melatonin ligand. Fundam Clin Pharmacol 13:253
Dubocovich ML, Yun K, Al-Ghoul WM, Benloucif S, Masana MI (1998) Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J 12:1211–1220
MacArthur JJ, Hunt AE, Gilette MU (1997) Melatonin action and signal transduction on the rat suprachiasmatic circadian clock: activation of protein kinase C at dusk and dawn. Endocrinology 138:627–634
Melatonin’s Effect on Neophobia in Mice
Delagrange P, Ting KN, Kopp C, Lahaye C, Lesieur D, Weibel L, Bennejean C, Renard R, Retton MC (1999) In vitro and in vivo antagonist properties of S 22153, a new melatonin ligand. Fundam Clin Pharmacol 13:253
Hughes RN (1968) Behaviour of male and female rats with a free choice of two environments differing in novelty. Anim Behav 16:92–96
Kopp C, Vogel E, Rettori MC, Delagrange P, Guardiola-Lamaître B, Misslin R (1999a) Effects of melatonin on neophobic responses in different strain of mice. Pharmacol Biochem Behav 63:521–526
Kopp C, Vogel E, Rettori MC, Delagrange P, Renard P, Lesieur D, Misslin R (1999b) Antagonistic effects of S22153, a new mt1 and MT2 receptor ligand, on the neophobia-reducing properties of melatonin in BALB/c mice. Pharmacol Biochem Behav 64:131–136
Melanophore Stimulating Hormone
Boehm M, Schiller M, Luger TA (2006) Non-pigmentary actions of alpha-melanocyte-stimulating hormone–lessons from the cutaneous melanocortin system [review]. Cell Mol Biol 52(2):61–68
Butler AA (2006) The melanocortin system and energy balance. Peptides 27(2):281–290
Catania A, Colombo G, Rossi C, Carlin A, Sordi A, Lonati C, Turcatti F, Leonardi P, Grieco P, Gatti S (2006) Antimicrobial properties of alpha-MSH and related synthetic melanocortins. Sci World J 6:1241–1246
Fehm HL, Born J, Peters A (2004) Glucocorticoids and melanocortins in the regulation of body weight in humans. Horm Metab Res 36(6):360–364
Hadley ME, Dorr RT (2006) Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides 27(4):230–921
Humphreys MH (2007) Cardiovascular and renal actions of melanocyte-stimulating hormone peptides. Curr Opin Nephrol Hypertens 16(1):32–38
Millington GW (2006) Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clin Exp Dermatol 31(3):407–412
Nargund RP, Strack AM, Fong TM (2006) Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J Med Chem 49(14):4035–4043, PMID: 16821763
Slominski A, Wortsman J (2000) Neuroendocrinology of the skin. Endocr Rev 21(5):457–487
Skin Darkening in Whole Amphibia
Hunt G (1995) Melanocyte-stimulating hormone: a regulator of human melanocyte physiology. Pathobiology 63:12–21
Inouye K, Otsuka H (1987) ACTH: structure-function relationship. In: Li CH (ed) Hormonal proteins and peptides, vol XIII. Academic, New York, pp 1–29
Landgrebe FW, Waring H (1950) Biological assay of the melanophore expanding hormone from the pituitary. In: Emmens CW (ed) Hormone assay. Academic, New York, pp 141–171
Landgrebe FW, Waring H (1962) Melanophore-expanding activity. In: Dorfman RI (ed) Methods in hormone research, vol II. Academic, New York, pp 517–558
Sandow J, Geiger R, Vogel HG (1977) Pharmacological effects of a short chain ACTH-analogue. Naunyn Schmiedebergs Arch Pharmacol 297(Suppl II):162
Assay in Isolated Amphibian Skin
Bagutti C, Eberle AN (1993) Synthesis and biological properties of a biotinylated derivative of ACTH1–17 for MSH receptor studies. J Recept Res 13:229–244
Celis ME, Taleisnik S, Walter R (1971) Regulation of formation and proposed structure of the factor inhibiting the release of melanocyte-stimulating hormone. Proc Natl Acad Sci U S A 68:1428–1433
Kastin AJ, Viosca A, Schally AV (1969) Assay of mammalian MSH release-regulating factors. In: Proceedings of the workshop conference: hypophysiotropic hormones of the hypothalamus: assay and chemistry. Tucson
Landgrebe FW, Waring H (1950) Biological assay of the melanophore expanding hormone from the pituitary. In: Emmens CW (ed) Hormone assay. Academic, New York, pp 141–171
Landgrebe FW, Waring H (1962) Melanophore-expanding activity. In: Dorfman RI (ed) Methods in hormone research, vol II. Academic, New York, pp 517–558
Sahm UG, Olivier GWJ, Branch SK, Moss SH, Pouton CW (1993) Influence of α-MSH terminal amino acids on binding affinity and biological activity in melanoma cells. Peptides 15:441–446
Sahm UG, Olivier GWJ, Branch SK, Moss SH, Pouton CW (1994) Synthesis and biological evaluation of α-MSH analogues substituted with alanine. Peptides 15:1297–1302
Sahm UG, Olivier GWJ, Branch SK, Moss SH, Pouton CW (1996) Receptor binding affinities and biological activities of linear and cyclic melanocortins in B16 murine melanoma cells expressing the native MC1 receptor. J Pharm Pharmacol 48:197–200
Schuler W, Schär B, Desaulles P (1963) Zur Pharmakologie eines ACTH-wirksamen, vollsynthetischen Polypeptids, des b1-24-Corticotropins, Ciba 30920-Ba, Synacthen. Schweiz Med Wschr 93:1027–1030
Shizume K, Lerner AB, Fitzpatrick TB (1954) In vitro bioassay for the melanocyte stimulating hormone. Endocrinology 54:553–560
Siegrist W, Eberle AN (1986) In situ melanin assay for MSH using mouse B16 melanoma cells in culture. Anal Biochem 159:191–197
Trendelenburg P (1926) Weitere Versuche über den Gehalt des Liquor cerebrospinalis an wirksamen Substanzen des Hypophysenhinterlappens. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 114:255–261
Vogel HG (1965) Evaluation of synthetic peptides with ACTH-Activity. Acta Endocrinol Suppl 100:34
Vogel HG (1969) Tierexperimentelle Untersuchungen über synthetische Peptide mit Corticotropinaktivität. A: Vergleich mit dem III Int Standard für Corticotropin. Arzneimittelforschung 19:20–24
Binding to the Melanocortin Receptor
Adan RAH, Cone RD, Burbach JPH, Gispen WH (1994) Differential effects of melanocortin peptides on neural melanocortin receptors. Mol Pharmacol 46:1182–1190
Bagutti C, Stolz B, Albert R, Bruns C, Pless J, Eberle AN (1993) [111In]DTPA-labeled analogues of α-MSH for the detection of MSH receptors in vitro and in vivo. Ann N Y Acad Sci 680:445–447
Chhajlani V, Wikberg JES (1992) Molecular cloning of a novel human melanocyte stimulating hormone receptor cDNA. FEBS Lett 309:417–420
Chhajlani V, Muceniece R, Wikberg JES (1993) Molecular cloning of a novel human melanocortin receptor. Biochem Biophys Res Commun 195:866–873
Cone RD, Lu D, Koppula S, Vage DI, Klungland H, Boston B, Chen W, Orth DN, Pouton C, Kesterson RA (1996) The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res 51:287–317
Desarnaud F, Labbe O, Eggerickx D, Vassart G, Parmentier M (1994) Molecular cloning, functional expression and pharmacological characterization of a mouse melanocortin receptor gene. Biochem J 299:367–373
Erskine-Grout ME, Olivier GWJ, Lucas P, Sahm UG, Branch SK, Moss SH, Notarianni LJ, Pouton CW (1996) Melanocortin probes for the melanoma MC1 receptor: synthesis, receptor binding and biological activity. Melanoma Res 6:89–94
Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (1997) Role of melanocortin neurons in feeding and agouti obesity syndrome. Nature 386:165–168
Fathi Z, Iben LG, Parker RM (1995) Cloning, expression, and tissue distribution of a fifth melanocortin receptor subtype. Neurochem Res 20:107–113
Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, Del Valle J, Yamada T (1993a) Molecular cloning of a novel melanocortin receptor. J Biol Chem 268:8246–8250
Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson SJ, Del Valle J, Yamada T (1993b) Molecular cloning, expression, and gene location of a fourth melanocortin receptor. J Biol Chem 268:15174–15179
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier RL, Gu W, Hesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141
Kask A, Rago L, Mutulis F, Pahkla R, Wikberg JES, Schioth HB (1998a) Selective antagonist for the melanocortin-4 receptor (HS014) increases food uptake in free-feeding rats. Biochem Biophys Res Commun 245:90–93
Kask A, Mutulis F, Muceniece R, Pahkla R, Mutule I, Wikberg JS, Rago L, Schioth HB (1998b) Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo. Endocrinology 139:5006–5014
Labbé O, Desarnaud F, Eggerickx D, Vassart G, Parmentier M (1994) Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. Biochemistry 93:4543–4549
Peng PJ, Sahm UG, Doherty RVM, Kinsman RG, Moss SH, Pouton CW (1997) Binding and biological activity of C-terminally modified melanocortin peptides: a comparison of their actions at rodent MC1 and MC3 receptors. Peptides 18:1001–1008
Quillan JM, Sadée W (1996) Structure-based search for peptide ligands that cross-react with melanocortin receptors. Pharm Res 13:1624–1630
Sahm UG, Qarawi MA, Olivier GWJ, Ahmed AHR, Branch SK, Moss SH, Pouton CW (1994) The melanocortin (MC3) receptor from rat hypothalamus: photoaffinity labelling and binding of alanine-substituted analogues. FEBS Lett 350:29–32
Sahm UG, Olivier GWJ, Branch SK, Moss SH, Pouton CW (1996) Receptor binding affinities and biological activities of linear and cyclic melanocortins in B16 murine melanoma cells expressing the native MC1 receptor. J Pharm Pharmacol 48:197–200
Schiöth HB, Muceniece R, Wikberg JES, Chhajlani V (1995) Characterization of melanocortin receptor subtypes by radioligand binding analysis. Eur J Pharmacol 288:311–317
Schiöth HB, Chhajlani V, Muceniece R, Klusa V, Wikberg JES (1996a) Major pharmacological distinction of the ACTH receptor from other melanocortin receptors. Life Sci 59:797–801
Schiöth HB, Muceniece R, Wikberg JES (1996b) Characterization of the melanocortin 4 receptor by radioligand binding. Pharmacol Toxicol 79:161–165
Schiöth HB, Muceniece R, Larsson M, Mutulis F, Szardenings M, Prusis P, Lindeberg G, Wikberg JES (1997a) Binding of cyclic and linear MSH core peptides to the melanocortin receptor subtypes. Eur J Pharmacol 319:369–373
Schiöth HB, Müceniece R, Mutulis F, Prusis P, Lindeberg G, Sharma SD, Hruby VJ, Wikberg JE (1997b) Selectivity of cyclic [d-Nal7] and d-Phe7] substituted MSH analogues for the melanocortin receptor subtypes. Peptides 18:1009–1013
Schiöth HB, Mutulis F, Muceniece R, Prusis P, Wikberg JES (1998a) Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on the binding to the human melanocortin receptor subtypes. Eur J Pharmacol 349:359–366
Schiöth HB, Mutulis F, Muceniece R, Prusis P, Wikberg JES (1998b) Discovery of novel melanocortin4 receptor selective MSH analogues. Br J Pharmacol 124:75–82
Skuladottir GV, Jonsson L, Skarphedinsson JO, Mutulis F, Muceniece R, Raine A, Mutule I, Helgason J, Prusis J, Wikberg JES, Schioth HB (1999) Long term orexigenic effect of a novel melanocortin-4 receptor selective antagonist. Br J Pharmacol 126:27–34
Strand FL (1999) New vistas for melanocortins. finally an explanation for their pleiotropic function. In: Sandman CA, Chronwall BM, Strand FL, Flynn FW, Beckwith B, Nachman RJ (eds) Neuropeptides. Structure and function in biology and behavior. Ann N Y Acad Sci 897:1–16
Melanocortin Peptides
Adan RA, van Dijk G (2006) Melanocortin receptors as drug targets for disorders of energy balance. CNS Neurol Disord Drug Targets 5(3):251–261
Adan RA, Tiesjema B, Hillebrand JJ, la Fleur SE, Kas MJ, de Krom M (2006) The MC4 receptor and control of appetite. Br J Pharmacol 149(7):815–827
Bjorbaek C, Hollenberg AN (2002) Leptin and melanocortin signaling in the hypothalamus. Vitam Horm 65:281–311
Cai M, Mayorov AV, Ying J, Stankova M, Trivedi D, Cabello C, Hruby VJ (2005) Design of novel melanotropin agonists and antagonists with high potency and selectivity for human melanocortin receptors. Peptides 26(8):1481–1485
Cone RD (2006) Studies on the physiological functions of the melanocortin system. Endocr Rev 27(7):736–749
Deboer MD, Marks DL (2006a) Cachexia: lessons from melanocortin antagonism. Trends Endocrinol Metab 17(5):199–204
DeBoer MD, Marks DL (2006b) Therapy insight: use of melanocortin antagonists in the treatment of cachexia in chronic disease. Nat Clin Pract Endocrinol Metab 2(8):459–466
Della-Fera MA, Baile CA (2005) Roles for melanocortins and leptin in adipose tissue apoptosis and fat deposition. Peptides 26(10):1782–1787
Eves PC, MacNeil S, Haycock JW (2006) alpha-Melanocyte stimulating hormone, inflammation and human melanoma. Peptides 27(2):444–452
Fan W, Voss-Andreae A, Cao WH, Morrison SF (2005) Regulation of thermogenesis by the central melanocortin system. Peptides 26(10):1800–1813
Gantz I, Fong TM (2003) The melanocortin system. Am J Physiol 284(3):E468–E474
Garcia-Borron JC, Sanchez-Laorden BL, Jimenez-Cervantes C (2005) Melanocortin-1 receptor structure and functional regulation. Pigment Cell Res 18(6):393–410
Getting SJ (2006) Targeting melanocortin receptors as potential novel therapeutics. Pharmacol Ther 111(1):1–15
Lin JY, Fisher DE (2007) Melanocyte biology and skin pigmentation. Nature 445(7130):843–850
Maaser C, Kannengiesser K, Kucharzik T (2006) Role of the melanocortin system in inflammation. Ann N Y Acad Sci 1072:123–134
Martin NM, Smith KL, Bloom SR, Small CJ (2006) Interactions between the melanocortin system and the hypothalamo-pituitary-thyroid axis. Peptides 27(2):333–339
Myers MG Jr (2004) Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res 59:287–304
Padwal RS, Majumdar SR (2007) Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 369(9555):71–77
Todorovic A, Haskell-Luevano C (2005) A review of melanocortin receptor small molecule ligands. Peptides 26(10):2026–2036
Relaxin
Bani D (1997) Relaxin: a pleiotropic hormone. Gen Pharmacol 28:13–22
Büllesbach EE, Schwabe C (1993) Mouse relaxin: synthesis and biological activity of the first relaxin with an unusual cross-linking pattern. Biochem Biophys Res Commun 196:311–319
Canova-Davis E, Baldonado IP, Teshima GM (1990) Characterization of chemically synthesized human relaxin by high-performance liquid chromatography. J Chromatogr 508:81–96
Coulson CC, Thorp JM Jr, Mayer DC, Cefalo RC (1996) Central hemodynamic effects of recombinant human relaxin in the isolated, perfused rat heart model. Obstet Gynecol 87:610–612
Evans BA, John M, Fowler KJ, Summers RJ, Crink M, Shine J, Tregear GW (1993) The mouse relaxin gene: nucleotide sequence and expression. J Mol Endocrinol 10:15–23
Goldsmith LT, Weiss G, Steinetz BG (1995) Relaxin and its role in pregnancy. Endocrinol Metab Clin North Am 24:171–186
Jockenhövel F, Peterson MA, Johnston PD, Swerdloff RS (1991) Directly iodinated rat relaxin as a tracer for use in radioimmunoassays. Eur J Clin Chem Clin Biochem 29:71–75
Klonisch T, Hombach-Klonisch S, Froehlich C, Kauffold J, Steger K, Steinetz BG, Fischer B (1999) Canine preprorelaxin: nucleic acid sequence and localization within the canine placenta. Biol Reprod 60:551–557
Layden SS, Tregear GW (1996) Purification and characterization of porcine prorelaxin. J Biochem Biophys Methods 31:69–80
Lucas C, Bald LN, Martin MC, Jaffe RB, Drolet DW, Mora-Worms M, Bennett G, Chen AB, Johnston PD (1989) An enzyme-linked immunoassay to study human relaxin in human pregnancy and in pregnant rhesus monkeys. J Endocrinol 120:449–457
Pusch W, Balvers M, Ivell R (1996) Molecular cloning and expression of the relaxin-like factor from the mouse testis. Endocrinology 137:3009–3013
Schwabe C, Büllesbach EE (1994) Relaxin: structures, functions, and nonevolution. FASEB J 8:1152–1160
Sherwood OD (1979) Relaxin. In: Jaffe BM, Behrman HR (eds) Methods of hormone radioimmunoassay. Academic, New York, pp 785–886
Steinetz BG, Büllesbach EE, Godsmith LT, Schwabe C, Lust G (1996) Use of synthetic canine relaxin to develop a rapid homologous radioimmunoassay. Biol Reprod 54:1252–1260
Taylor MJ, Clark CL (1989) Analysis of relaxin release by cultured porcine luteal cells using a reverse hemolytic plaque assay: effects of arachidonic acid, cyclo- and lipoxygenase blockers, phospholipase A2, and melittin. Endocrinology 125:1389–1397
Taylor MJ, Clark CL (1992a) Basic fibroblast growth factor inhibits basal and stimulated relaxin secretion by cultured luteal cells: analysis by reverse hemolytic plaque assay. Endocrinology 130:1951–1956
Taylor MJ, Clark CL (1992b) Discordant secretion of relaxin by individual porcine large luteal cells: quantitative analysis by a reverse hemolytic plaque assay. J Endocrinol 134:77–83
Wade JD, Layden SS, Lambert PF, Kakouris H, Tregear GW (1994) Primate relaxin: synthesis of gorilla and rhesus monkey relaxins. J Protein Chem 13:315–321
Zarreh-Hoshyari-Khah MR, Einspanier A, Ivell R (1999) Differential splicing and expression of the relaxin-like factor gene in reproductive tissues of the marmoset monkey (Callithrix jacchus). Biol Reprod 60:445–453
Relaxin Bioassay by Pubic Symphysis Method in Guinea Pigs
Hisaw FL (1929) The corpus luteum hormone. I. Experimental relaxation of the pelvic ligaments of the guinea pig. Physiol Zool 2:59–79
Kroc RL, Steinetz BG, Beach VL, Stasilli NR (1956) Bioassay of relaxin extracts in guinea pigs and mice, using a reference standard. J Clin Endocrinol Metab 16:966
Kroc RL, Steinetz BG, Beach VL (1959) The effects of estrogens, progestagens, and relaxin in pregnant and nonpregnant laboratory rodents. Ann N Y Acad Sci 75:942–980
Steinetz BG, Lust G (1994) Inhibition of relaxin-induced pubic symphyseal ‘relaxation’ in guinea pigs by glycosaminoglycan polysulfates and pentosan polysulfate. Agents Actions 42:74–80
Steinetz BG, Beach VL, Kroc RL (1969a) Relaxin. In: Dorfman RI (ed) Methods in hormone research, vol II. Academic, New York, pp 559–589
Steinetz BG, Beach VL, Kroc RL (1969b) Bioassay of relaxin. In: Dorfman RI (ed) Methods in hormone research, vol IIA. Academic, New York, pp 481–513
Relaxin Bioassay in Mice
Bullesbach EE, Schwabe C (1996) The chemical synthesis of rat relaxin and the unexpectedly high potency of the synthetic hormone in the mouse. Eur J Biochem 241:533–537
Dorfman RI, Marsters RW, Dinerstein J (1953) Bioassay of relaxin. Endocrinology 52:204–214
Hall K (1948) Further notes on the action of oestrone and relaxin on the pelvis of the spayed mouse, including a single-dose test of potency of relaxin. J Endocrinol 5:314–321
Kroc RL, Steinetz BG, Beach VL (1959) The effects of estrogens, progestagens, and relaxin in pregnant and nonpregnant laboratory rodents. Ann N Y Acad Sci 75:942–980
Samuel CS, Coghlan JP, Bateman JF (1998) Effects of relaxin, pregnancy and parturition on collagen metabolism in the rat pubic symphysis. J Endocrinol 159:125–1178
Steinetz BG, Beach VL, Kroc RL, Stasilli NR, Nussbaum RE, Nemith PJ, Dunn RK (1960) Bioassay of relaxin using a reference standard: a simple and reliable method utilizing direct measurement of interpubic ligament formation in mice. Endocrinology 67:102–115
Steinetz BG, Beach VL, Kroc RL (1969a) Bioassay of relaxin. In: Dorfman RI (ed) Methods in hormone research, vol IIA. Academic, New York, pp 481–513
Steinetz BG, Beach VL, Kroc RL (1969b) Relaxin. In: Dorfman RI (ed) Methods in hormone research, vol II. Academic, New York, pp 559–589
Inhibition of Uterine Motility
Del Angel Meza AR, Beas-Zárate C, Alfaro FL, Morales-Villagran A (1991) A simple biological assay for relaxin measurement. Comp Biochem Physiol 99(C):35–39
Downing SJ, Hollingsworth M (1993) Action of relaxin on uterine contractions. A review. J Reprod Fertil 99:275–282
Downing SJ, Sherwood OD (1985) The physiological role of relaxin in the pregnant rat. III The influence of relaxin on cervical distensibility. Endocrinology 116:1215–1220
Felton LC, Frieden EH, Bryant HH (1953) The effects of ovarian extracts upon activity of the guinea pig uterus in situ. J Pharmacol Exp Ther 107:160–164
Porter DG, Downing SJ, Bradshaw JMC (1979) Relaxin inhibits spontaneous and prostaglandin-driven myometrial activity in anaesthetized rats. J Endocrinol 83:183–192
Steinetz BG, Beach VL, Kroc RL (1969) Bioassay of relaxin. In: Dorfman RI (ed) Methods in hormone research, vol IIA. Academic, New York, pp 481–513
Vu AL, Green CB, Roby KF, Soares MJ, Fei DTW, Chen AB, Kwok SCM (1993) Recombinant porcine prorelaxin produced in Chinese hamster ovary cells is biologically active. Life Sci 52:1055–1061
Wiqvist N, Paul KG (1958) Inhibition of the spontaneous uterine motility in vitro as a bioassay of relaxin. Acta Endocrinol 31:135–146
Relaxin Assay by Interstitial Collagenase Activity in Cultured Uterine Cervical Cells
Dean DD, Woessner JF Jr (1985) A sensitive specific assay for tissue collagenase using telopeptide-free 3H-acetylated collagen. Anal Biochem 148:174–181
Mushayandebvu TI, Rajabi MR (1995) Relaxin stimulates interstitial collagenase activity in cultured uterine cervical cells from nonpregnant and pregnant but not immature guinea pigs; estradiol-17β restores relaxin’s effect in immature cervical cells. Biol Reprod 53:1030–1037
Rajabi MR, Dean DD, Beydoun SN, Woessner JF Jr (1988) Elevated tissue levels of collagenase during dilatation of uterine cervix in human parturition. Am J Obstet Gynecol 159:971–976
Rajabi MR, Solomon S, Poole AR (1991) Biochemical evidence of collagenase-mediated collagenolysis as a mechanism of cervical dilatation in the guinea pig at parturition. Biol Reprod 45:764–772
Relaxin Receptor Binding
Bryant-Greenwood GD, Greenwood FC, Mercado-Simmen R, Weiss T, Yamamoto S, Ueno M, Arakaki R (1982) Relaxin secretion and relaxin receptors: the linkages. Ann N Y Acad Sci 380:100–110
Büllesbach EE, Schwabe C (1988) On the receptor binding site of relaxin. Int J Pept Protein Res 32:361–367
Büllesbach EE, Yang S, Schwabe C (1992) The receptor binding site of human relaxin II. A dual prong-binding mechanism. J Biol Chem 267:22957–22960
Mercado-Simmen RC, Bryant-Greenwood GD, Greenwood FC (1982a) Relaxin receptor in the rat myometrium: regulation by estrogen and relaxin. Endocrinology 110:220–226
Mercado-Simmen RC, Goodwin B, Ueno MS (1982b) Relaxin receptors in the myometrium and cervix of pig. Biol Reprod 26:120–128
Min G, Sherwood OD (1996) Identification of specific relaxin-binding cells in the cervix, mammary glands, nipples, small intestine, and skin of pregnant pigs. Biol Reprod 55:1243–1252
Osheroff PL, Phillips HS (1991) Autoradiographic localization of relaxin binding sites in rat brain. Proc Natl Acad Sci U S A 88:6413–6417
Segaloff A, Gabbard RB (1982) Preparation of fluoresceinylthiocarbamyl relaxin for the demonstration of relaxin receptors. Ann N Y Acad Sci 380:198–199
Yang S, Rembiesa B, Büllesbach EE, Schwabe C (1992) Relaxin receptors in mice: demonstration of ligand binding in symphyseal tissues and uterine membrane fragments. Endocrinology 130:179–185
Calcitonin Gene-Related Peptide
Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature (Lond) 289:240–244
Amara SG, Arriza JI, Swanson LW, Evans RM, Rosenfeld MG (1985) Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide. Science 229:1094–1097
Barakat A, Rosselin G, Marie J-C (1993) Characterization of specific calcitonin gene-related peptide receptors present in hamster pancreatic β-cells. Biosci Rep 13:221–231
Born W, Fischer A (1993) Calcitonin gene products: molecular biology, chemistry, and actions. Handb Exp Pharmacol 107:569–616
Brain SD, Hughes SR, Cambridge H, O’Driscoll G (1993) The contribution of calcitonin gene-related peptide (CGRP) to neurogenic vasodilator responses. Agents Actions 38(Special Issue I):C19–C21
Cadieux A, Monast NP, Pomerleau F, Fournier A, Lanoue C (1999) Bronchoprotector properties of calcitonin gene-related peptide in guinea pig and human airways: effect of pulmonary inflammation. Am J Respir Crit Care Med 159:235–243
Castellucci A, Maggi CA, Evangelista S (1993) Calcitonin gene-related peptide (CGRP)1 receptor mediates vasodilation in the rat isolated and perfused kidney. Life Sci 53:PL153–PL158
Champion HC, Akers DL, Santiago JA, Lambert DG, McNamara DB, Kadowitz PJ (1997) Analysis of the responses to human synthetic adrenomedullin and calcitonin gene-related peptides in the hindlimb vascular bed of the cat. Mol Cell Biochem 176:5–11
Chatzipantelli K, Goldberg RB, Howard GA, Roos BA (1996) Calcitonin gene-related peptide is an adipose-tissue neuropeptide with lipolytic actions. Endocrinol Metab 3:235–242
Clementi G, Amico-Roxas M, Caruso A, Cutuli VMC, Maugeri S, Prato A (1993) Protective effects of calcitonin gene-related peptide in different experimental models of gastric ulcers. Eur J Pharmacol 238:101–104
Clementi G, Caruso A, Prato A, De Bernardis E, Fiore CE, Amico-Roxas M (1994a) A role of nitric oxide in the anti-ulcer activity of calcitonin gene-related peptide. Eur J Pharmacol 256:R7–R8
Clementi G, Amico-Roxas M, Caruso A, Cutuli VMC, Prato A, Maugeri S, de Bernardis E, Scapagnini U (1994b) Effects of CGRP in different models of mouse ear inflammation. Life Sci 54:119–124
Dumont Y, Fournier A, St-Pierre S, Quirion R (1997) A potent and selective CGRP2 agonist, [Cys(Et)2.7]hCGRPα: comparison in prototypical CGRP1 and CGRP2 in vitro bioassays. Can J Physiol Pharmacol 75:671–676
Evangelista S, Renzi D (1997) A protective role for calcitonin gene-related peptide in water-immersion stress-induced gastric ulcers in rats. Pharmacol Res 35:347–350
Fleming NW, Lewis BK, White DA, Dretchen KL (1993) Acute effects of calcitonin gene-related peptide on the mechanical and electrical responses of the rat hemidiaphragm. J Pharmacol Exp Ther 265:1199–1204
Howitt SG, Poyner DR (1997) The selectivity and structural determinants of peptide antagonists at the CGRP receptor of rat, L6 myocytes. Br J Pharmacol 121:1000–1004
Kitamura K, Kanagawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Ato T (1993) Adrenomedullin, a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 192:553–560
Kurz V, von Gaudecker B, Kranz A, Krisch B, Mentlein R (1995) Calcitonin gene-related peptide and its receptor in the thymus. Peptides 16:1497–1503
Leighton B, Cooper GJS (1988) Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle. Nature 335:632–634
Li J, Matsuura JE, Waugh DJJ, Adrian TE, Abel PW, Manning MC, Smith DD (1997) Structure–activity studies on position 14 of human α-calcitonin gene-related peptide. J Med Chem 40:3071–3076
Lutz TA, Rossi R, Althaus J, Del Prete E, Scharrer E (1997) Evidence for a physiological role of central calcitonin gene-related peptide (CGRP) receptors in the control of food intake in rats. Neurosci Lett 230:159–162
Maggi CA, Giuliani S, Santicioli P (1995) CGRP inhibition of electromechanical coupling in the guinea-pig isolated rat pelvis. Naunyn Schmiedebergs Arch Pharmacol 352:529–537
McMurdo L, Lockhart JC, Ferrell WR (1997) Modulation of synovial blood flow by the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8–37. Br J Pharmacol 121:1075–1080
Meini S, Santicioli P, Maggi CA (1995) Propagation of impulses in the guinea-pig ureter and its blockade by calcitonin gene-related peptide (CGRP). Naunyn Schmiedebergs Arch Pharmacol 351:79–86
Menard DP, Van Rossum D, Kar S, St Pierre S, Sutak M, Jhamandas K, Quirion R (1996) A calcitonin gene-related peptide antagonists prevents the development of tolerance to spinal morphine analgesia. J Neurosci 16:2342–2351
Merchant NB, Dempsey DT, Grabowski MW, Rizzo M, Ritchie WP Jr (1994) Capsaicin-induced gastric mucosal hyperemia and protection: the role of calcitonin gene-related peptide. Surgery 116:419–425
Morley JE, Farr SA, Flood JF (1996) Peripherally administered calcitonin gene-related peptide decreases food intake in mice. Peptides 17:511–516
Morris HR, Panico M, Etienne T, Tippins J, Girgis SI, MacIntyre I (1984) Isolation and characterization of human calcitonin gene-related peptide. Nature 308:746–748
Nuki C, Kawasaki H, Takasaki K, Wada A (1994) Structure-activity study of chicken calcitonin gene-related peptide (CGRP) on vasorelaxation in rat mesenteric resistance vessels. Jpn J Pharmacol 65(2):99–105
Poyner DR (1992) Calcitonin-gene-related peptide: multiple actions, multiple receptors. Pharmacol Ther 56:23–51
Poyner DR (1997) Molecular pharmacology of receptors for calcitonin-gene-related peptide, amylin and adrenomedullin. Biochem Soc Trans 25:1032–1036
Poyner DR, Taylor GM, Tomlinson AE, Richardson AG, Smith DM (1999) Characterization of receptors for calcitonin gene-related peptide and adrenomedullin on the guinea pig vas deferens. Br J Pharmacol 126:1276–1282
Preibisz JJ (1993) Calcitonin gene-related peptide and regulation of human cardiovascular homeostasis. Am J Hypertens 6:434–450
Raddino R, Pela G, Manca C, Barbagallo M, D’Aloia A, Passeri M, Visioli O (1997) Mechanism of action of human calcitonin gene-related peptide in rabbit heart and human mammary arteries. J Cardiovasc Pharmacol 29:463–470
Rink TJ, Beaumont K, Koda J, Young AA (1993) Structure and biology of amylin. Trends Pharmacol Sci 14:113–118
Sakai K, Saito K, Akima M (1998) Synergistic effect of calcitonin gene-related peptide on adenosine-induced vasodepression in rats. Eur J Pharmacol 344:153–159
Schaible H-G (1996) On the role of tachykinins and calcitonin gene-related peptide in the spinal mechanisms of nociception and in the induction and maintenance of inflammation-evoked hyperexcitability in spinal cord neurons (with special reference to nociception in joints). In: Kumazawa T, Kruger L, Mizumura K (eds) Progress in brain research, vol 113. Elsevier Science, Amsterdam, pp 423–441
Smith DD, Li J, Wang Q, Murphy RF, Adrian TE, Elias Y, Bockman CS, Abel PW (1993) Synthesis and biological activity of C-terminally truncated fragments of human α-calcitonin gene-related peptide. J Med Chem 36:2536–2541
Tomobe YI, Ishikawa T, Goto K (1998) Enhanced endothelium-independent vasodilator response to calcitonin gene-related peptide in hypertensive rats. Eur J Pharmacol 35:351–355
Van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21:649–678
Wang F, Millet I, Bottomly K, Vignery A (1992) Calcitonin gene-related peptide inhibits interleukin 2 production by murine T lymphocytes. J Biol Chem 267:21052–21057
Wimalawansa SJ (1996) Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev 17:533–585
Wisskirchen FM, Burt RP, Marshall I (1998) Pharmacological characterization of CGRP receptors of the rat pulmonary artery and inhibition of twitch responses f the rat deferens. Br J Pharmacol 123:1673–1683
Receptor Binding of CGRP
Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergma DJ, Li Y (1996) A cDNA encoding the calcitonin gene-related peptide type 1 receptor. J Biol Chem 271:11325–11329
Born W, Fischer JA (1993) Calcitonin gene products: molecular biology, chemistry, and actions. Handb Exp Pharmacol 107:569–616c
Dennis T, Fournier A, St. Pierre S, Quirion R (1989) Structure-activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity. J Pharmacol Exp Ther 251:718–725
Dennis T, Fournier A, Guard S, St. Pierre S, Quirion R (1991) Calcitonin gene-related peptide (hCGRP alpha) binding sites in nucleus accumbens. Atypical structural requirements and marked phylogenetic differences. Brain Res 539:59–66
Juaneda C, Dumont Y, Quirion R (2000) The molecular pharmacology of CGRP and related peptide receptor subtypes. Trends Pharmacol Sci 21:432–438
Muff R, Stangl D, Born W, Fischer JA (1992) Comparison of a calcitonin gene-related peptide receptor in a human neuroblastoma cell line (SK-N-MC) and a calcitonin receptor in a human breast carcinoma cell line (T47D). Ann N Y Acad Sci 657:106–116
Muff R, Born W, Fischer JA (1995) Receptors for calcitonin, calcitonin gene related peptide, amylin, and adrenomedullin. Can J Physiol Pharmacol 73:963–967
Poyner DR (1997) Molecular pharmacology of receptors for calcitonin-gene-related peptide, amylin and adrenomedullin. Biochem Soc Trans 25:1032–1036
Poyner DR, Taylor GM, Tomlinson AE, Richardson AG, Smith DM (1999) Characterization of receptors for calcitonin gene-related peptide and adrenomedullin on the guinea pig vas deferens. Br J Pharmacol 126:1276–1282
Quirion R, van Rossum D, Dumont Y, St. Pierre S, Fournier R (1992) Characterization of CGRP1 and CGRP2 receptor subtypes. Ann N Y Acad Sci 657:88–105
Schindler M, Doods HN (2002) Binding properties of the novel, non-peptide CGRP receptor antagonist radioligand, [3H]BIBN4096BS. Eur J Pharmacol 442:187–193
Van Rossum D, Ménard DP, Fournier A, St-Pierre S, Quirion R (1994) Binding profile of a selective calcitonin gene-related peptide (CGRP) receptor antagonist ligand, [125I-Tyr]hCGRP8–37, in rat brain and peripheral tissues. J Pharmacol Exp Ther 269:846–853
Van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21:649–678
Wimalawansa SJ (1989) A sensitive and specific radioreceptor assay for calcitonin gene-related peptide. J Neuroendocrinol 1:15–18
Wimalawansa SJ (1996) Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev 17:533–585
Wimalawansa SJ, El-Kholy AA (1993) Comparative study of distribution and biochemical characterization of brain calcitonin gene-related peptide receptors in five different species. Neuroscience 54:513–519
Inhibin
De Kretser DM, Robertson DM (1989) The isolation and physiology of inhibin and related proteins. Biol Reprod 40:33–47
Forage RG, Ring JM, Brown RW et al (1986) Cloning and sequence analysis of cDNA species coding for the two subunits of inhibin from bovine follicular fluid. Proc Natl Acad Sci U S A 83:3091–3095
Franchimont P, Verstraelen-Proyard J, Hazee-Hagelstein MT, Renard C, Demoulin A, Bourguignon JP, Hustin J (1979) Inhibin: from concept to reality. In: Munson PL, Diczfalusy E, Glover J, Olson RE (eds) Vitamins and hormones, vol 37, Advances in research and applications. Academic, New York, pp 243–302
Franchimont P, Hazee-Hagelstein MT, Jaspar JM, Charlet-Renard C, Demoulin A (1989) Inhibin and related peptides: mechanisms of action and regulation of secretion. J Steroid Biochem 32:193–197
Gaines Das RE, Rose M, Zanelli JM (1992) International collaborative study by in vitro bioassays of the first International Standard for porcine inhibin. J Reprod Fertil 96:803–814
Halvorson LM, DeCherney AH (1996) Inhibin, activin, and follistatin in reproductive medicine. Fertil Steril 65:459–469
Mason AJ, Niall HD, Seeburg PH (1986) Structure of two human ovarian inhibins. Biochem Biophys Res Commun 135:957–964
McGullagh DR (1932) Dual endocrine activity of the testes. Science 76:19–20
Moore A, Krummen LA, Mather JP (1994) Inhibins, activins, their binding proteins and receptors: interactions underlying paracrine activity in the testis. Mol Cell Endocrinol 100:81–86
Robertson DM (1991) Transforming growth factor-β/inhibin family. Baillieres Clin Endocrinol Metab 5:615–634
Robertson DM, Giacometti MS, de Kretser DM (1986) The effects of inhibin purified from bovine follicular fluid in several in vitro pituitary culture systems. Mol Cell Endocrinol 46:29–36
Robertson DM, Foulds LM, Prosk M, Hedger MP (1992) Inhibin/activin β-subunit monomer: isolation and characterization. Endocrinology 130:1680–1687
Rose MP, Gaines Das RE (1996) International collaborative study by in vitro bioassays and immunoassays of the first international standard for inhibin, human recombinant. Biologicals 24:1–18
Stewart AG, Millborrow HM, Ring JM, Crowther CE, Forage RG (1986) Human inhibin genes: genomic characterization and sequencing. FEBS Lett 206:329–334
Tierney ML, Goss NH, Tomkins SM, Kerr DB, Pitt DE, Forage RG, Robertson DM, Hearn MTW, de Kretser DM (1990) Physicochemical and biological characterization of recombinant human inhibin A. Endocrinology 126:3268–3270
Tio S, Koppenaal D, Bardin CW, Cheng CY (1994) Purification of gonadotropin surge-inhibiting factor from Sertoli cell-enriched medium. Biochem Biophys Res Commun 199:1229–1236
Vale W, Rivier C, Hsueh AJW, Campen C, Meunier H, Bicsak T, Vaughan J, Corrigan A, Bardin W, SawchenkoP PF, Yu J, Plotsky P, Spiess J, Rivier J (1986) Chemical and biological characterization of inhibin family of proteins. Recent Prog Horm Res 44:1–34
Woodruff TK, Besecke LM, Groome N, Draper LB, Schwartz NB, Weiss J (1996) Inhibin A and inhibin B are inversely correlated to follicle-stimulating hormone, yet are discordant during the follicular phase of the rat estrus cycle, and inhibin A is expressed in a sexually dimorphic manner. Endocrinology 137:5463–5467
In Vitro Bioassay for Inhibin
Allenby G, Foster PMD, Sharpe RM (1991) Evaluation of changes in the secretion of immunoreactive inhibin by adult rat seminiferous tubules in vitro as an indicator of early toxicant action on spermatogenesis. Fundam Appl Toxicol 16:710–724
Blumenfeld Z, Ritter M, Shen-Orr Z, Shariki K, Ben-Shahar M, Haim N (1998) Inhibin A concentrations in the sera of young women during and after chemotherapy for lymphoma: correlation with ovarian toxicity. Am J Reprod Immunol 39:33–40
Brown JL, Dahl KD, Chakraborty PK (1991) Effects of follicular fluid administration on serum bioactive and immunoreactive FSH concentrations and compensatory testosterone secretion in hemicastrated adult rats. J Androl 12:221–225
Demura R, Suzuki T, Tajima S, Kubo O, Yoshimoto T, Demura H (1996) Inhibin α, β A and β B subunit messenger ribonucleic acid levels in cultured rat pituitary: studies by a quantitative RT-PCR. Endocr J 43:403–410
Gaines Das RE, Rose M, Zanelli JM (1992) International collaborative study by in vitro bioassays of the first International Standard for porcine inhibin. J Reprod Fertil 96:803–814
Hertan R, Farnworth PG, Fitzsimmons KL, Robertson DM (1999) Identification of high affinity binding sites for inhibin on ovine pituitary cells in culture. Endocrinology 140:6–12
Jakubowiak A, Janecki A, Steinberger A (1989) Similar effects of inhibin and cycloheximide on gonadotropin release in superfused pituitary cell cultures. Biol Reprod 41:454–463
Knight PG, Muttukrishna S (1994) Measurement of dimeric inhibin using a modified two-site immunoradiometric assay specific for oxidized (Met O) inhibin. J Endocrinol 141:417–425
Knight PG, Groome M, Beard AJ (1991) Development of a two-site immunoradiometric assay for dimeric inhibin using antibodies against chemically synthesized fragments of the α and β subunit. J Endocrinol 129:R9–R12
Magoffin DA, Jakimiuk AJ (1998) Inhibin A, inhibin B and activin A concentrations in follicular fluid from women with polycystic ovary syndrome. Hum Reprod 13:2693–2698
Mason AJ, Farnworth PG, Sullivan J (1996) Characterization and determination of the biological activities of noncleavable high molecular weight forms of inhibin A and activin A. Mol Endocrinol 10:1055–1065
Munson PJ, Rodbard D (1980) Ligand, a versatile computerised approach for characterization of ligand binding systems. Anal Biochem 107:220–239
Robertson DM, Prisk M, McMaster JW, Irby DC, Findlay JK, de Kretser DM (1991) Serum FSH-suppressing activity of human recombinant inhibin A in male and female rats. J Reprod Fertil 91:321–328
Robertson D, Burger HG, Sullivan J, Cahir N, Groome N, Poncelet E, Franchimont P, Woodruff T, Mather CP (1996) Biological and immunological characterization of inhibin forms in human plasma. J Clin Endocrinol Metab 81:669–676
Rose MP, Gaines Das RE (1996) International collaborative study by in vitro bioassays and immunoassays of the first international standard for inhibin, human recombinant. Biologicals 24:1–18
Simpson BJB, Hedger MP, de Kretser DM (1992) Characterisation of adult Sertoli cell cultures from cryptorchid rats: inhibin secretion in response to follicle-stimulating hormone. Mol Cell Endocrinol 87:167–177
Wallace EM, Crossley JA, Ritoe SC, Aitken DA, Spencer K, Groome NP (1998) Evolution of an inhibin A ELISA method: implications for Down’s syndrome screening. Ann Clin Biochem 35:656–664
Wenstrom KD, Owen J, Chu DC, Boots L (1997) Elevated second-trimester dimeric inhibin A levels identify Down syndrome pregnancies. Am J Obstet Gynecol 177:992–996
Wreford NG, O’Connor AE, de Kretser DM (1994) Gonadotropin-suppressing activity of human recombinant inhibin in the male rat is age dependent. Biol Reprod 50:1066–1071
Activin
Dalkin AC, Haisenleder DJ, Yasin M, Gilrain JT, Marshall JC (1996) Pituitary activin receptor subtypes and follistatin gene expression in female rats: differential regulation by activin and follistatin. Endocrinology 137:548–554
De Paolo LV (1997) Inhibins, activins, follistatins: the saga continues. Proc Soc Exp Biol Med 214:328–339
Eto Y, Tsuji T, Takezawa M, Takano S, Tokagawa Y, Shibai H (1987) Purification and characterization of erythroid differentiation factor (EDF) isolated from human leukemia cell line THP-1. Biochem Biophys Res Commun 142:1095–1103
Hashimoto O, Yamato K, Koseki T, Ohguchi M, Ishisaki A, Shoji H, Nakamura T, Hayashi Y, Sugino H, Nishihara T (1998) The role of activin type I receptors in activin A-induced growth arrest and apoptosis in mouse B-cell hybridoma cells. Cell Signal 10:743–749
Hötten G, Neidhardt H, Schneider C, Pohl J (1995) Cloning of a new member of the TGF-β family: a putative new activin β C chain. Biochem Biophys Res Commun 206:608–613
Lee W, Mason AJ, Schwall R, Szonyi E, Mather JP (1989) Secretion of activin by interstitial cells in the testis. Science 243:396–398
Ling N, Ying SY, Ueno N, Shimasaki S, Etsch F, Hott M, Guillemin R (1986) Pituitary FSH is released by a homodimer of the beta subunit from the two forms of inhibin. Nature 321:779–782
Loveland KL, McFarlane JR, de Kretser DM (1996) Expression of activin β C subunit mRNA in reproductive tissue. J Mol Endocrinol 17:61–65
MacConnell LA, Lawson MA, Mellon PL, Roberts VJ (1999) Activin A regulation of gonadotropin-releasing hormone synthesis and release in vitro. Neuroendocrinology 70:246–254
Mason AJ (1988) Structure and recombinant expression of human inhibin and activin. In: Nonsteroidal gonadal factors: physiological roles and possibilities in contraceptive development. Jones Institute, Norfolk, pp 1–19
Mason AJ, Berkemeier LM, Schmelzer CH, Schwall RH (1989) Activin B: precursor sequences, genomic structure and in vitro activities. Mol Endocrinol 3:1352–1358
Mather JP, Attie KM, Woodruff DK, Rice GC, Phillips DM (1990) Activin stimulates spermatogonial proliferation in germ-Sertoli cell cocultures from immature rat testis. Endocrinology 127:3206–3214
Nakamura T, Asashima M, Eto Y, Takio K, Uchiyama H, Moriya M, Ariizumi T, Yashiro T, Sugino K, Titani K, Sugino H (1992) Isolation and characterization of native activin B. J Biol Chem 267:16385–16389
Thomsen G, Woolf T, Whitman M, Solkol S, Vaughan J, Vale W et al (1990) Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures. Cell 63:485–493
Vale W, Rivier J, McClintock R, Corrigan A, Woo W, Karr D, Spiess J (1986) Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid. Nature 321:776–779
In Vitro Bioassay for Activin
Attardi B, Miklos J (1990) Rapid stimulatory effect of activin-A on messenger RNA encoding the follicle-stimulating hormone b-subunit in pituitary cell cultures. Mol Endocrinol 4:721–726
Brosh N, Sternberg D, Honigswachs-Sha’anani J, Lee BC, Shav-Tal Y, Tzehoval E, Shulman LM, Toledo J, Hacham Y, Carmi P, Jiang W, Sasse J, Horn F, Burstein Y, Zipori D (1995) The plasmacytoma growth inhibitor restrictin-P is an antagonist of interleukin 6 and interleukin 11. Identification as a stroma-derived activin A. J Biol Chem 270:29594–29600
Carroll RS, Corrigan AZ, Vale W, Chin WW (1991) Activin stabilizes follicle-stimulating hormone-beta messenger ribonucleic acid levels. Endocrinology 129:1721–1726
Demura R, Suzuki T, Tajima S, Mitsuhashi S, Odagiri E, Demura H (1993) Activin and inhibin secretion by cultured porcine granulosa cells is stimulated by FSH and LH. Endocr J 40:447–451
De Winter JP, Timmermann MA, Vanderstichele HMJ, Klaij IA, Grootenhuis AJ, Rommerts FFG, de Jong FH (1992) Testicular Leydig cells in vitro secrete only inhibin α-subunits, whereas Leydig cell tumors can secrete bioactive inhibin. Mol Cell Endocrinol 83:105–115
Knight PG, Muttukrishna S, Groome NP (1996) Development and application of a two-site enzyme immunoassay for the determination of ‘total’ activin-A concentrations in serum and follicular fluid. J Endocrinol 148:267–279
LaPolt PS, Soto D, Su J-G, Campen CA, Vaughan J, Vale W, Hsueh AJW (1989) Activin stimulation of inhibin secretion and messenger RNA levels in cultured granulosa cells. Mol Endocrinol 3:1666–1673
Laskov R, Scharff MD (1970) Synthesis, assembly, and secretion of gamma globulin by mouse myeloma cells. I. Adaptation of the Mervin plasma cell tumor-11 to culture, cloning and characterization of gamma globulin subunits. J Exp Med 131:515–541
Liu ZH, Shintani Y, Wakatsuki M, Sakamoto Y, Harada K, Zhang CY, Saito S (1996) Regulation of immunoreactive activin A secretion from cultured rat anterior pituitary cells. Endocr J 43:39–44
McFarlane JR, Foulds LM, Pisciotta A, Robertson DM, de Kretser DM (1996) Measurement of activin in biological fluids by radioimmunoassay, utilizing dissociating agents to remove the interference of follistatin. Eur J Endocrinol 134:481–489
Miyamoto S, Irahara M, Ushigoe K, Kuwahara A, Sugino H, Aono T (1999) Effects of activin on hormone secretion by single female rat pituitary cells: analysis by cell immunoblot assay. J Endocrinol 161:375–382
Nieuwkoop PD, Faber J (1967) Normal table of Xenopus laevis. Daudlin, Amsterdam
Peng C, Ohno T, Koh LY, Chen VTS, Leung PCK (1999) Human ovary and placenta express messenger RNA for multiple activin receptors. Life Sci 64:983–994
Phillips DJ, Brauman JN, Mason AJ, de Kretser DM, Hedger MP (1999) A sensitive and specific in vitro bioassay for activin using a mouse plasmacytoma cell line, MPC-11. J Endocrinol 162:111–116
Robertson DM, Foulds LM, Prisk M, Hedger MP (1992) Inhibin/activin β-subunit monomer: isolation and characterization. Endocrinology 130:345–351
Saito S, Nakamura T, Titani K, Sugino H (1991) Production of activin-binding protein by rat granulosa cells in vitro. Biochem Biophys Res Commun 176:413–422
Schwall RH, Lai C (1991) Erythroid differentiation assays for activin. Methods Enzymol 198:340–346
Shao L, Frigon NL Jr, Sehy DW, Yu AL, Lofgren J, Schwall R, Yu J (1992) Regulation of production of activin A in human marrow stromal cells and monocytes. Exp Hematol 20:1235–1242
Shintani Y, Takada Y, Yamasaki R, Saito S (1991) Radioimmunoassay for activin A/EDF. Method and measurement of immunoreactive A/EDF levels in various biological materials. J Immunol Methods 137:267–274
Uchimaru K, Motokura T, Takahashi S, Sakurai T, Asano S, Yamashita T (1995) Bone marrow stromal cells produce and respond to activin A: interactions with basic fibroblast growth factor and platelet-derived growth factor. Exp Hematol 23:613–618
Wuytens G, Verschueren K, de Winter JP, Gajendran N, Beek L, Devos K, Bosman F, de Waele P, Andries M, van den Eijnden-van Raaij AJM, Smith JC, Huylebroeck D (1999) Identification of two amino acids in activin A that are important for biological activity and binding to the activin type II receptors. J Biol Chem 274:9821–9827
Yamashita T, Takahashi S, Ogata E (1992) Expression of activin A/erythroid differentiation factor in murine bone marrow stromal cells. Blood 79:304–307
Follistatin
Bohnsack BL, Szabo M, Kilen SM, Tam DH, Schwartz HB (2000) Follistatin suppresses steroid-enhanced follicle-stimulating hormone release in vitro in rats. Biol Reprod 62:636–641
De Winter JP, ten Dijke P, de Vries CJM, van Achterberg TAE, Sugino H, de Waele P, Huylebroeck D, Verschueren K, van den Eijnden-van Raaij AJM (1996) Follistatins neutralize activin bioactivity by inhibition of activin binding to its type II receptors. Mol Cell Endocrinol 116:105–114
Inouye S, Guo Y, de Paolo L, Shimonaka M, Ling N, Shimasaki S (1991) Recombinant expression of human follistatin with 315 and 288 amino acids: chemical and biological comparison with native porcine follistatin. Endocrinology 129:815–822
Namakura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H (1990) Activin-binding protein from rat ovary is follistatin. Science 247:836–838
Patel K (1998) Follistatin. Int J Biochem Cell Biol 30:1087–1093
Robertson DM, Klein R, de Vos FL, McLachlan RI, Wettenhall REH, Hearn MTW, Burger HG, de Kretser DM (1987) The isolation of polypeptides with FSH suppressing activity from bovine follicular fluid which are structurally different to inhibin. Biochem Biophys Res Commun 149:744–749
Shimonaka M, Inouye S, Shimasaki S, Ling N (1991) Follistatin binds to both activin and inhibin through the common beta-subunit. Endocrinology 128:3313–3315
Sugino K, Kurosawa N, Nakamura T, Takio K, Shimasaki S, Guillemin R (1993) Molecular heterogeneity of follistatin, an activin-binding protein. J Biol Chem 268:15579–15587
Ueno N, Ling N, Ying SY, Esch F, Shimasaki S, Guillemin R (1987) Isolation and partial characterization of follistatin: a single-chain, monomeric protein that inhibits the release of follicle-stimulating hormone. Proc Natl Acad Sci U S A 84:8282–8286
Ying SY, Becker A, Swanson G, Tan P, Ling N, Esch F, Ueno N, Shimasaki S, Guillemin R (1987) Follistatin specifically inhibits pituitary follicle-stimulating hormone release in vitro. Biochem Biophys Res Commun 149:133–139
Immunoassay for Follistatin
DePaolo LV, Shimonaka M, Schwall RH, Ling N (1991) In vivo comparison of the follicle-stimulating hormone-suppressing activity of follistatin and inhibin in ovariectomized rats. Endocrinology 128:668–674
Evans LW, Muttukrishna S, Groome NP (1998) Development, validation and application of an ultra-sensitive immunoassay for human follistatin. J Endocrinol 156:275–282
Galfre G, Milstein C (1981) Preparation of monoclonal antibodies: strategies and procedures. In: Langone JJ, Vunakis HV (eds) Methods in enzymology. Academic, New York, pp 3–36
Groome NP, Illingworth PJ, O’Brien M, Priddle J, Weaver K, McNeilly AS (1995) Quantification of inhibin pro-αC-containing forms in human serum by a new ultrasensitive two-site enzyme-linked immunosorbent assay. J Clin Endocrinol Metab 80:2926–2932
Ishikawa A, Imagawa M, Hashida S, Yoshitake S, Hamaguchi Y, Ueno T (1983) Enzyme labeling of antibodies and their fragments for enzyme immunoassay and immunocytochemistry. J Immunoassay 4:209–327
Nakamura T, Hasegawa Y, Sugino K, Kogawa K, Titani K, Sugino H (1992) Follistatin inhibits activin-induced differentiation of rat follicular granulosa cells in vitro. Biochim Biophys Acta 1135:103–109
Xiao S, Robertson DM, Findlay JK (1992) Effects of activin and follicle-stimulating hormone (FSH)-suppressing protein/follistatin on FSH receptors and differentiation of cultured rat granulosa cells. Endocrinology 131:1009–1016
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Sandow, J. (2015). Effects on Different Peptide Hormones. In: Hock, F. (eds) Drug Discovery and Evaluation: Pharmacological Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27728-3_84-1
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