Abstract
TRPC (canonical transient receptor potential) channels are the closest mammalian homologs of Drosophila TRP and TRP-like channels. TRPCs are rather nonselective Ca2+ permeable cation channels and affect cell functions through their ability to mediate Ca2+ entry into cells and their action to collapse the plasma membrane potentials. In neurons the latter function leads to action potentials. The mammalian genome codes for seven TRPCs of which TRPC2 is the largest with the most restricted pattern of expression and has several alternatively spliced variants. Expressed in model cells, TRPC2 mediates both receptor- and store depletion-triggered Ca2+ entry. TRPC2 is unique among TRPCs in that its complete gene has been lost from the Old World monkey and human genomes, in which its remnants constitute a pseudogene. Physiological roles for TRPC2 have been studied in mature sperm and the vomeronasal sensory system. In sperm, TRPC2 is activated by the sperm’s interaction with the oocyte’s zona pellucida, leading to entry of Ca2+ and activation of the acrosome reaction. In the vomeronasal sensory organ (VNO), TRPC2 was found to constitute the transduction channel activated through signaling cascade initiated by the interaction of pheromones with V1R and V2R G protein-coupled receptors on the dendrites of the sensory neurons. V1Rs and V2Rs, the latter working in conjunction with class I MHC molecules, activate Gi- and Go-type G proteins which in turn trigger activation of TRPC2, initiating an axon potential that travels to the axonal terminals. The signal is then projected to the glomeruli of the auxiliary olfactory bulb from where it is carried first to the amygdala and then to higher cortical cognition centers. Immunocytochemistry and gene deletion studies have shown that (1) the V2R-Go-MHCIb-β2m pathway mediates male aggressive behavior in response to pheromones; (2) the V1R-Gi2 pathway mediates mating partner recognition, and (3) these differences have an anatomical correlate in that these functional components are located in anatomically distinct compartments of the VNO. Interestingly, these anatomically segregated signaling pathways use a common transduction channel, TRPC2.
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Arnoult C, Cardullp RA, Lemos JR, Florman HM (1996) Activation of mouse sperm T-type Ca2+ channels by adhesion to the egg zona pellucida. Proc Natl Acad Sci USA 93:13004–13009
Arnoult C, Kazam IG, Visconti PE, Kopf GS, Villaz M, Florman HM (1999) Control of the low voltage-activated calcium channel of mouse sperm by egg ZP3 and by membrane hyperpolarization during capacitation. Proc Natl Acad Sci USA 96:6757–6762
Bakalyar HA, Reed RR (1990) Identification of a specialized adenylyl cyclase that may mediate odorant detection. Science 250:1403–1406
Berghard A, Buck LB (1996) Sensory transduction in vomeronasal neurons: evidence for G alpha o, G alpha i2, and adenylyl cyclase II as major components of a pheromone signaling cascade. J Neurosci 16:909–918
Berghard A, Buck LB, Liman ER (1996) Evidence for distinct signaling mechanisms in two mammalian olfactory sense organs. Proc Natl Acad Sci USA 93:2365–2369
Birnbaumer L, Zhu X, Jiang M, Boulay G, Peyton M, Vannier B, Brown D, Platano D, Sadeghi H, Stefani E, Birnbaumer M (1996) On the molecular basis and regulation of cellular capacitative calcium entry: roles for Trp proteins. Proc Natl Acad Sci USA 93:15195–15202
Birnbaumer L, Boulay G, Brown D, Jiang M, Dietrich A, Mikoshiba K, Zhu X, Qin N (2000) Mechanism of capacitative Ca2+ entry (CCE): interaction between IP3 receptor and TRP links the internal calcium storage compartment to plasma membrane CCE channels. Recent Prog Horm Res 55:127–162
Birnbaumer L, Yildirim E, Abramowitz J (2003) A comparison of the genes coding for canonical TRP channels and their M, V, and P relatives. Cell Calcium 33:419–432
Bleil JD, Wassarman PM (1983) Sperm-egg interactions in the mouse: sequence of events and induction of the acrosome reaction by a zona pellucida glycoprotein. Dev Biol 95:317–324
Buck L, Axel R (1991) A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65:175–187
Buck LB (2000) The molecular architecture of odor and pheromone sensing in mammals. Cell 100:611–618
Castellano LE, Trevio CL, Rodriguez D, Serrano CJ, Pacheco J, Tsutsumi V, Felix R, Darszon A (2003) Transient receptor potential (TRPC) channels in human sperm: expression, cellular localization and involvement in the regulation of flagellar motility. FEBS Lett 541:69–74
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824
Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398:436–441
Chu X, Tong Q, Cheung JY, Wozney J, Conrad K, Mazack V, Zhang W Stahl R, Barber DL, Miller BA (2004) Interaction of TRPC2 and TRPC6 in erythropoietin modulation of calcium influx. J Biol Chem 279:10514–10522
Devary O, Heichal O, Blumenfeld A, Cassel D, Suss E, Barash S, Rubinstein CT, Minke B, Selinger Z (1987) Coupling of photoexcited rhodopsin to inositol phospholipid hydrolysis in fly photoreceptors. Proc Natl Acad Sci USA 84:6939–6943
Dulac C (2000) Sensory coding of pheromone signals in mammals. Curr Opin Neurobiol 10:511–518
Dulac C, Axel R (1995) A novel family of genes encoding putative pheromone receptors in mammals. Cell 83:195–206
Dulac C, Torello AT (2003) Molecular detection of pheromone signals in mammals: from genes to behaviour. Nat Rev Neurosci 4:551–562
Endo Y, Lee MA, Kopf GS (1987) Evidence for the role of a guanine nucleotide-binding regulatory protein in the zona pellucida-induced mouse sperm acrosome reaction. Dev Biol 119:210–216
Firestein S, Werblin F (1989) Odor-induced membrane currents in vertebrate-olfactory receptor neurons. Science 244:79–82
Firestein S, Shepherd GM, Werblin FS (1990) Time course of the membrane current underlying sensory transduction in salamander olfactory receptor neurons. J Physiol 430:135–158
Firestein S, Zufall F, Shepherd GM (1991) Single odor-sensitive channels in olfactory receptor neurons are also gated by cyclic nucleotides. J Neurosci 11:3565–3572
Florman HM, Tombes RM, First NL, Babcock DF (1989) An adhesion-associated agonist from the zona pellucida activates H-protein-promoted elevations of internal Ca2+ and pH that mediate mammalian sperm acrosomal exocytosis. Dev Biol 135:133–146
Florman HM, Corron ME, Kim TD, Babcock DF (1992) Activation of voltage-dependent calcium channels of mammalian sperm is required for zona pellucida-induced acrosomal exocytosis. Dev Biol 152:304–314
Grimm C, Kraft R, Sauerbruch S, Schultz G, Harteneck C (2003) Molecular and functional characterization of the melastatin-related cation channel TRPM3. J Biol Chem 278:21493–21501
Guler AD, Lee HS, Iida T, Shimizu I, Toinaga M, Caterina M (2002) Heat-evoked activation of the ion channel, TRPV4. J Neurosci 22:6408–6414
Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J, Shimizu N, Kurose H, Okada Y, Imoto K, Mori Y (2002) LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9:163–173
Herrada G, Dulac C (1997) A novel family of putative pheromone receptors in mammals with a topographically organized and sexually dimorphic distribution. Cell 90:763–773
Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, Bindels RJ (1999) Molecular identification of the apical calcium channel in 1,25-dihyroxyvitamin D3-responsive epithelia. J Biol Chem 274:8375–8378
Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397:259–263
Hofmann T, Schaefer M, Schultz G, Gudermann T (2000) Cloning, expression and subcellular localization of two novel splice variants of mouse transient receptor potential channel 2. Biochem J 351:115–122
Hofmann T, Chubanov V, Guderman T, Montell C (2003) TRPM5 is a voltage-modulated and Ca2+-activated monovalent selective cation channel. Curr Biol 13:1153–1158
Hotta Y, Benzer S (1970) Genetic dissection of the Drosophila nervous system by means of mosaics. Proc Natl Acad Sci USA 67:1156–1163
Ishii T, Hirota J, Mombaerts P (2003) Combinatorial coexpression of neural and immune multigene families in mouse vomeronasal sensory neurons. Curr Biol 13:394–400
Jia C, Halpern M (1996) Subclasses of vomeronasal receptor neurons: differential expression of G proteins (Gi2-alpha and Go-alpha) and segregated projections to the accessory olfactory bulb. Brain Res 719:117–128
Jones DT, Reed RR (1989) Golf: an olfactory neuron specific-G protein involved in odorant signal transduction. Science 244:790–795
Jovine L, Darie CC, Litscher ES, Wassarman PM (2005) Zona pellucida domain proteins. Annu Rev Biochem 74:83–114
Jungnickel MK, Marrero H, Birnbaumer L, Lemos JR, Florman HM (2001) TRP2 is essential for Ca2+ entry into mouse sperm triggered by egg ZP3. Nat Cell Biol 3:499–502
Kanzaki M, Zhang YQ, Mashima H, Li L, Shibata H, Kojima I (1999) Translocation of a calcium-permeable cation channel induced by insulin-like growth factor I. Nat Cell Biol 1:165–170
Keverne EB (1999) The vomeronasal organ. Science 286:716–720
Kiselyov K, Xu X, Mozhayeva G, Kuo T, Pessah I, Mignery G, Zhu X, Birnbaumer L, Muallem S (1998) Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature 396:478–482
Launay P, Fleig A, Perraud AL, Scharenberg AM, Penner R, Kinet JP (2002) TRPM4 is a Ca2+-activated nonselective cation channel mediating membrane depolarization. Cell 109:397–407
Lee MA, Storey BT (1989) Endpoint of first stage of zona pellucida-induced acrosome reaction in mouse spermatozoa characterized by acrosomal H+ and Ca2+ permeability: population and single cell kinetics. Gamete Res 24:303–326
Leinders-Zufall T, Brennan P, Widmayer P, S P C, Maul-Pavicic A, Jager M, Li XH, Breer H, Zufall F, Boehm T (2004) MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306:1033–1037
Leypold BG, Yu CR, Leinders-Zufall T, Kim MM, Zufall F, Axel R (2002) Altered sexual and social behaviors in trp2 mutant mice. Proc Natl Acad Sci USA 99:6376–6381
Liman ER, Buck LB (1994) A second subunit of the olfactory cyclic nucleotide-gated channel confers high sensitivity to cAMP. Neuron 13:611–621
Liman ER, Corey DP (1996) Electrophysiological characterization of chemosensory neurons from the mouse vomeronasal organ. J Neurosci 16:4625–4637
Liman ER, Innan H (2003) Relaxed selective pressure on an essential component of pheromone transduction in primate evolution. Proc Natl Acad Sci USA 100:3328–3232
Liman ER, Corey DP, Dulac C (1999) TRP2: a candidate transduction channel for mammalian pheromone sensory signaling. Proc Natl Acad Sci USA 96:5791–5796
Loconto J, Papes F, Chang E, Stowers L, Jones EP, Takada T, Kumanovics A, Fischer Lindahl K, Dulac C (2003) Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112:607–618
Lucas P, Ukhahov K, Leinders-Zufall T, Zufall F (2003) A diacylglycerol-gated cation channel in vomeronasal neuron dendrites is impaired in TRPC2 mutant mice: mechanism of pheromone transduction. Neuron 40:551–561
Matsunami H, Buck LB (1997) A multigene family encoding a diverse array of putative pheromone receptors in mammals. Cell 90:775–784
McKemy DD, Neuhauser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58
Menco BP, Carr VM, Ezeh PI, Liman ER, Yankova MP (2001) Ultrastructural localization of G-proteins and the channel protein TRP2 to microvilli of rat vomeronasal receptor cells. J Comp Neurol 438:468–489
Miller DJ, Macek MB, Shur BD (1992) Complementarity between sperm surface beta-1,4-galactosyltransferase and egg-coat ZP3 mediates sperm-egg binding. Nature 357:589–593
Monteilh-Zoller MK, Hermosura MC, Nadler MJ, Scharenberg AM, Penner R, Fleig A (2003) TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions. J Gen Physiol 121:49–60
Nakamura T, Gold GH (1987) A cyclic nucleotide-gated conductance in olfactory receptor cilia. Nature 325:442–444
Nilius B, Mahieu F, Prenen J, Janssens A, Owsianik G, Vennekens R, Voets T (2006) The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-bisphosphate. EMBO J 25:467–478
O’Toole CM, Arnoult C, Darszon A, Steinhardt RA, Florman HM (2000) Ca2+ entry through store-operated channels in mouse sperm is initiated by egg ZP3 and drives the acrosome reaction. Mol Biol Cell 11:1571–1584
Pace U, Lancet D (1986) Olfactory GTP-binding protein: signal-transducing polypeptide of vertebrate chemosensory neurons. Proc Natl Acad Sci USA 83:4947–4951
Pace U, Hanski E, Salomon Y, Lancet D (1985) Odorant-sensitive adenylate cyclase may mediate olfactory reception. Nature 316:255–258
Pak WL, Grossfield J, Arnold K (1970) Mutant of the visual pathway of Drosophila melanogaster. Nature 227:518–520
Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P, Bevan S, Patapoutian A (2002) A heat-sensitive TRP channel expressed in keratinocytes. Science 296:2046–2049
Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schimitz C, Stokes AJ, Zhu Q, Bessman MJ, Penner R, Kinet JP, Scharenberg AM (2001) ADP-ribose gating of the calciumpermeable LTRPC2 channel revealed by Nudix motif homology. Nature 411:595–599
Prescott ED, Julius D (2003) A modulator PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300:1284–1288
Primakoff P, Myles P (2002) Penetration, adhesion, and fusion in mammalian sperm-egg interaction. Science 296:2183–2185
Raming K, Krieger J, Strotmann J, Boekhoff I, Kubick S, Baumstark C, Breer H (1993) Cloning and expression of odorant receptors. Nature 361:353–356
Ressler KJ, Sullivan SL, Buck LB (1993) A zonal organization of odorant receptor gene expression in the olfactory epithelium. Cell 73:597–609
Ressler KJ, Sullivan SL, Buck LB (1994) Information coding in the olfactory system: evidence for a stereotyped and highly organized epitope map in the olfactory bulb. Cell 79:1245–1255
Runnels LW, Yue L, Clapham DE (2002) The TRPM7 channel is inactivated by PIP2 hydrolysis. Nat Cell Biol 4:329–336
Saito H, Mimmack ML, Keverne EB, Kishimoto J, Emson PC (1998) Isolation of mouse vomeronasal receptor genes and their co-localization with specific G-protein messenger RNAs. Brain Res Mol Brain Res 60:215–227
Selinger Z, Minke B (1988) Inositol lipid cascade of vision studied in mutant flies. Cold Spring Harb Symp Quant Biol 53:333–341
Shirakawa H, Miyazaki S (1999) Spatiotemporal characterization of intracellular Ca2+ rise during acrosome reaction of mammalian spermatozoa induced by zona pellucida. Dev Biol 208:70–78
Sklar PB, Anholt RR, Snyder SH (1986) The odorant-sensitive adenylate cyclase of olfactory receptor cells: differential stimulation by distinct classes of odorants. J Biol Chem 261:15538–15543
Smith GD, Gunthrope MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin JP, Ooi L, Egerton J, Charles KJ, Smart D, Randall AD, Anand D, Davis JB (2002) TRPV3 is a temperature sensitive vanilloid receptor-like protein. Nature 418:186–190
Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829
Stowers L, Holy TE, Meister M, Dulac C, Koentges G (2002) Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science 295:1493–1500
Stamboulian S, Moutin MJ, Treves S, Pochon N, Grunwald D, Zorzato F, De Waard M, Ronjat M, Arnoult C (2005) Junctate, an inositol 1,4,5-trisphosphate receptor associated protein, is present in rodent sperm and binds TRPC2 and TRPC5 but not TRPC1 channels. Dev Biol 286:326–337
Sutton KA, Jungnickel MK, Wang Y, Cullen K, Lambert S, Florman HM (2004) Enkurin is a novel calmodulin and TRPC channel binding protein in sperm. Dev Biol 274:426–435
Talavera K, Yasumatsu K, Voets T, Droogmans G, Shigemura N, Ninomiya Y, Margolskee RF, Nilius B (2005) Heat activation of TRPM5 underlies thermal sensitivity of sweet taste. Nature 438:1022–1025
Tang J, Lin Y, Zhang Z, Tikunova S, Birnbaumer L, Zhu MX (2001) Identification of common binding sites for calmodulin and inositol 1,4,5-trisphosphate receptors on the carboxyl termini of trp channels. J Biol Chem 276:21303–21310
Treves S, Franzini-Armstrong C, Moccagatta L, Arnoult C, Grasso C, Schrum A, Ducreux S, Zhu MX, Mikoshiba K, Girard T, Smida-Rezgui S, Ronjat M, Zorzato F (2004) Junctate is a key element in calcium entry induced by activation of IP3 receptors and/or calcium store depletion. J Cell Biol 166:537–548
Trevino CL, Serrano CJ, Beltran C, Felix R, Darszon A (2001) Identification of mouse trp homologs and lipid rafts from spermatogenic cells and sperm. FEBS Lett 509:119–125
Trotier D, MacLeod P (1983) Intracellular recordings from salamander olfactory receptor cells. Brain Res 268:225–237
Vannier B, Peyton M, Boulay G, Brown D, Qin N, Jiang M, Zhu X, Birnbaumer L (1999) Mouse trp2, the homologue of the human trpc2 pseudogene, encodes mTrp2, a store depletion-activated capacitative Ca2+ entry channel. Proc Natl Acad Sci USA 96:2060–2064
Vassar R, Chao SK, Sitcheran R, Nunez JM, Vosshall LB, Axel R (1994) Topographic organization of sensory projections to the olfactory bulb. Cell 79:981–991
Walensky LD, Snyder SH (1995) Inositol 1,4,5-trisphosphate receptors selectively localized to the acrosomes of mammalian sperm. J Cell Biol 130:857–869
Ward CR, Kopf GS (1993) Molecular events mediating sperm activation. Dev Biol 158:9–34
Ward CR, Storey BT, Kopf GS (1992) Activation of a Gi protein in mouse sperm membranes by solubilized proteins of the zona pellucida, the egg’s extracellular matrix. J Biol Chem 267:14061–14067
Wassarman PM (1999) Mammalian fertilization: molecular aspects of gamete adhesion, exocytosis, and fusion. Cell 96:175–183
Wehage E, Eisfeld J, Heiner I, Eberhard J, Zitt C, Luckhoff A (2002) Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. J Biol Chem 277:23150–23156
Wilde MW, Ward CR, Kopf GS (1992) Activation of a G-protein in mouse sperm by the zona pellucida, an egg-associated extracellular matrix. Mol Reprod Dev 31:297–306
Wissenbach U, Schroth G, Philipp S, Flockerzi V (1998) Structure and mRNA expression of a bovine trp homologue related to mammalian trp2 transcripts. FEBS Lett 429:61–66
Yildirim E, Dietrich A, Birnbaumer L (2003) The mouse C-type transient receptor potential 2 (TRPC2) channel: alternative splicing and calmodulin binding to its N terminus. Proc Natl Acad Sci USA 100:2220–2225
Zhu X, Jiang M, Peyton MJ, Boulay G, Hurst R, Stefani E, Birnbaumer L (1996) trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell 85:661–671
Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457
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Yildirim, E., Birnbaumer, L. (2007). TRPC2: Molecular Biology and Functional Importance. In: Flockerzi, V., Nilius, B. (eds) Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology, vol 179. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-34891-7_3
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