Abstract
Canonical transient receptor potential 4 (TRPC4) forms non-selective cation channels that contribute to phospholipase C-dependent Ca2+ entry into cells following stimulation of G protein coupled receptors and receptor tyrosine kinases. Moreover, the channels are regulated by pertussis toxin-sensitive Gi/o proteins, lipids, and various other signaling mechanisms. TRPC4-containing channels participate in the regulation of a variety of physiological functions, including excitability of both gastrointestinal smooth muscles and brain neurons. This review is to present recent advances in the understanding of physiology and development of small molecular modulators of TRPC4 channels.
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Montell C. The TRP superfamily of cation channels. Sci STKE, 2005, 2005: re3
Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem, 2007, 76: 387–417
Zitt C, Halaszovich CR, Luckhoff A. The TRP family of cation channels: probing and advancing the concepts on receptor-activated calcium entry. Prog Neurobiol, 2002, 66: 243–264
Vazquez G, Wedel BJ, Aziz O, Trebak M, Putney JW Jr. The mammalian TRPC cation channels. Biochim Biophys Acta, 2004, 1742: 21–36
Eder P, Schindl R, Romanin C, Groschner K. Protein-protein interactions in TRPC channel complexes. In: Liedtke WB, Heller S, eds. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press, 2007. Chapter 24
Poteser M, Graziani A, Rosker C, Eder P, Derler I, Kahr H, Zhu MX, Romanin C, Groschner K. TRPC3 and TRPC4 associate to form a redox-sensitive cation channel. Evidence for expression of native TRPC3-TRPC4 heteromeric channels in endothelial cells. J Biol Chem, 2006, 281: 13588–13595
Ma X, Cheng KT, Wong CO, O’Neil RG, Birnbaumer L, Ambudkar IS, Yao X. Heteromeric TRPV4-C1 channels contribute to store-operated Ca2+ entry in vascular endothelial cells. Cell Calcium, 2011, 50: 502–509
Kobori T, Smith GD, Sandford R, Edwardson JM. The transient receptor potential channels TRPP2 and TRPC1 form a heterotetramer with a 2:2 stoichiometry and an alternating subunit arrangement. J Biol Chem, 2009, 284: 35507–35513
Liu X, Bandyopadhyay BC, Singh BB, Groschner K, Ambudkar IS. Molecular analysis of a store-operated and 2-acetyl-sn-glycerol-sensitive non-selective cation channel. Heteromeric assembly of TRPC1-TRPC3. J Biol Chem, 2005, 280: 21600–21606
Schindl R, Fritsch R, Jardin I, Frischauf I, Kahr H, Muik M, Riedl MC, Groschner K, Romanin C. Canonical transient receptor potential (TRPC) 1 acts as a negative regulator for vanilloid TRPV6-mediated Ca2+ influx. J Biol Chem, 2012, 287: 35612–35620
Philipp S, Cavalie A, Freichel M, Wissenbach U, Zimmer S, Trost C, Marquart A, Murakami M, Flockerzi V. A mammalian capacitative calcium entry channel homologous to Drosophila TRP and TRPL. EMBO J, 1996, 15: 6166–6171
McKay RR, Szymeczek-Seay CL, Lievremont JP, Bird GS, Zitt C, Jungling E, Luckhoff A, Putney JW Jr. Cloning and expression of the human transient receptor potential 4 (TRP4) gene: localization and functional expression of human TRP4 and TRP3. Biochem J, 2000, 351: 735–746
Schaefer M, Plant TD, Obukhov AG, Hofmann T, Gudermann T, Schultz G. Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. J Biol Chem, 2000, 275: 17517–17526
Schaefer M, Plant TD, Stresow N, Albrecht N, Schultz G. Functional differences between TRPC4 splice variants. J Biol Chem, 2002, 277: 3752–3759
Tang J, Lin Y, Zhang Z, Tikunova S, Birnbaumer L, Zhu MX. Identification of common binding sites for calmodulin and inositol 1,4,5-trisphosphate receptors on the carboxyl termini of trp channels. J Biol Chem, 2001, 276: 21303–21310
Trost C, Bergs C, Himmerkus N, Flockerzi V. The transient receptor potential, TRP4, cation channel is a novel member of the family of calmodulin binding proteins. Biochem J, 2001, 355: 663–670
Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, Dehoff MH, Schwarz MK, Seeburg PH, Muallem S, Worley PF. Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell, 2003, 114: 777–789
Greka A, Navarro B, Oancea E, Duggan A, Clapham DE. TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nat Neurosci, 2003, 6: 837–845
Garcia RL, Schilling WP. Differential expression of mammalian TRP homologues across tissues and cell lines. Biochem Biophys Res Commun, 1997, 239: 279–283
Mery L, Magnino F, Schmidt K, Krause KH, Dufour JF. Alternative splice variants of hTrp4 differentially interact with the C-terminal portion of the inositol 1,4,5-trisphosphate receptors. FEBS Lett, 2001, 487: 377–383
Miehe S, Bieberstein A, Arnould I, Ihdene O, Rutten H, Strubing C. The phospholipid-binding protein SESTD1 is a novel regulator of the transient receptor potential channels TRPC4 and TRPC5. J Biol Chem, 2010, 285: 12426–12434
Jeon JP, Hong C, Park EJ, Jeon JH, Cho NH, Kim IG, Choe H, Muallem S, Kim HJ, So I. Selective Galphai subunits as novel direct activators of transient receptor potential canonical (TRPC)4 and TRPC5 channels. J Biol Chem, 2012, 287: 17029–17039
Odell AF, Van Helden DF, Scott JL. The spectrin cytoskeleton influences the surface expression and activation of human transient receptor potential channel 4 channels. J Biol Chem, 2008, 283: 4395–4407
Fanning AS, Anderson JM. Protein-protein interactions: PDZ domain networks. Curr Biol, 1996, 6: 1385–1388
Tang Y, Tang J, Chen Z, Trost C, Flockerzi V, Li M, Ramesh V, Zhu MX. Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. J Biol Chem, 2000, 275: 37559–37564
Mery L, Strauss B, Dufour JF, Krause KH, Hoth M. The PDZ-interacting domain of TRPC4 controls its localization and surface expression in HEK293 cells. J Cell Sci, 2002, 115: 3497–3508
Freichel M, Suh SH, Pfeifer A, Schweig U, Trost C, Weissgerber P, Biel M, Philipp S, Freise D, Droogmans G, Hofmann F, Flockerzi V, Nilius B. Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4−/− mice. Nat Cell Biol, 2001, 3: 121–127
Tiruppathi C, Freichel M, Vogel SM, Paria BC, Mehta D, Flockerzi V, Malik AB. Impairment of store-operated Ca2+ entry in TRPC4−/− mice interferes with increase in lung microvascular permeability. Circ Res, 2002, 91: 70–76
Obukhov AG, Nowycky MC. TRPC4 can be activated by G-protein-coupled receptors and provides sufficient Ca2+ to trigger exocytosis in neuroendocrine cells. J Biol Chem, 2002, 277: 16172–16178
Munsch T, Freichel M, Flockerzi V, Pape HC. Contribution of transient receptor potential channels to the control of GABA release from dendrites. Proc Natl Acad Sci USA, 2003, 100: 16065–16070
El-Hassar L, Hagenston AM, D’Angelo LB, Yeckel MF. Metabotropic glutamate receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca2+ wave-dependent activation of SK and TRPC channels. J Physiol, 2011, 589: 3211–3229
Phelan KD, Mock MM, Kretz O, Shwe UT, Kozhemyakin M, Greenfield LJ, Dietrich A, Birnbaumer L, Freichel M, Flockerzi V, Zheng F. Heteromeric canonical transient receptor potential 1 and 4 channels play a critical role in epileptiform burst firing and seizure-induced neurodegeneration. Mol Pharmacol, 2012, 81: 384–392
Phelan K, Shwe U, Abramowitz J, Wu H, Rhee S, Howell M, Gottschall P, Freichel M, Flockerzi V, Birnbaumer L, Zheng F. Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Mol. Pharmacol, 2013, 83: 429–438
Stroh O, Freichel M, Kretz O, Birnbaumer L, Hartmann J, Egger V. NMDA receptor-dependent synaptic activation of TRPC channels in olfactory bulb granule cells. J Neurosci, 2012, 32: 5737–5746
Torihashi S, Fujimoto T, Trost C, Nakayama S. Calcium oscillation linked to pacemaking of interstitial cells of Cajal: requirement of calcium influx and localization of TRP4 in caveolae. J Biol Chem, 2002, 277: 19191–19197
Walker RL, Koh SD, Sergeant GP, Sanders KM, Horowitz B. TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal. Am J Physiol Cell Physiol, 2002, 283: C1637–1645
Tsvilovskyy VV, Zholos AV, Aberle T, Philipp SE, Dietrich A, Zhu MX, Birnbaumer L, Freichel M, Flockerzi V. Deletion of TRPC4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo. Gastroenterology, 2009, 137: 1415–1424
Antigny F, Koenig S, Bernheim L, Frieden M. During post-natal human myogenesis, normal myotube size requires TRPC1- and TRPC4-mediated Ca2+ entry. J Cell Sci, 2013, 126: 2525–2533
Beck B, Lehen’kyi V, Roudbaraki M, Flourakis M, Charveron M, Bordat P, Polakowska R, Prevarskaya N, Skryma R. TRPC channels determine human keratinocyte differentiation: new insight into basal cell carcinoma. Cell Calcium, 2008, 43: 492–505
Weick JP, Austin Johnson M, Zhang SC. Developmental regulation of human embryonic stem cell-derived neurons by calcium entry via transient receptor potential channels. Stem Cells, 2009, 27: 2906–2916
von Spiczak S, Muhle H, Helbig I, de Kovel CG, Hampe J, Gaus V, Koeleman BP, Lindhout D, Schreiber S, Sander T, Stephani U. Association study of TRPC4 as a candidate gene for generalized epilepsy with photosensitivity. Neuromol Med, 2010, 12: 292–299
Jung C, Gené GG, Tomás M, Plata C, Selent J, Pastor M, Fandos C, Senti M, Lucas G, Elosua R, Valverde MA. A gain-of-function SNP in TRPC4 cation channel protects against myocardial infarction. Cardiovasc Res, 2011, 91: 465–471
Qiu J, Fang Y, Ronnekleiv OK, Kelly MJ. Leptin excites proopiomelanocortin neurons via activation of TRPC channels. J Neurosci, 2010, 30: 1560–1565
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao GL, Tsvetkov E, Rodig SJ, Van’t Veer A, Meloni EG, Carlezon WA Jr, Bolshakov VY, Clapham DE. Essential role for TRPC5 in amygdala function and fear-related behavior. Cell, 2009, 137: 761–772
Riccio A, Li Y, Tsvetkov E, Gapon S, Yao GL, Smith KS, Engin E, Rudolph U, Bolshakov VY, Clapham DE. Decreased anxiety-like behavior and G?q/11-dependent responses in the amygdala of mice lacking TRPC4 channels. J Neurosci, 2014, 34: 3653–3667
Plant TD, Schaefer M. TRPC4 and TRPC5: receptor-operated Ca2+-permeable nonselective cation channels. Cell Calcium, 2003, 33: 441–450
Otsuguro K, Tang J, Tang Y, Xiao R, Freichel M, Tsvilovskyy V, Ito S, Flockerzi V, Zhu MX, Zholos AV. Isoform-specific inhibition of TRPC4 channel by phosphatidylinositol 4,5-bisphosphate. J Biol Chem, 2008, 283: 10026–10036
Kim H, Jeon JP, Hong C, Kim J, Myeong J, Jeon JH, So I. An essential role of PI(4,5)P2 for maintaining the activity of the transient receptor potential canonical (TRPC)4?. Pflugers Arch, 2013, 465: 1011–1021
Runnels LW, Yue L, Clapham DE. The TRPM7 channel is inactivated by PIP2 hydrolysis. Nat Cell Biol, 2002, 4: 329–336
Liu B, Qin F. Functional control of cold- and menthol-sensitive TRPM8 ion channels by phosphatidylinositol 4,5-bisphosphate. J Neurosci, 2002, 25: 1674–1681
Rohács T, Lopes CM, Michailidis I, Logothetis DE. PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nat Neurosci, 2005, 8: 626–634
Zhang Z, Okawa H, Wang Y, Liman ER. Phosphatidylinositol 4,5-bisphosphate rescues TRPM4 channels from desensitization. J Biol Chem, 2005, 280: 39185–39192
Imai Y, Itsuki K, Okamura Y, Inoue R, Mori MX. A self-limiting regulation of vasoconstrictor-activated TRPC3/C6/C7 channels coupled to PI(4,5)P2-diacylglycerol signalling. J Physiol, 2012, 590: 1101–1119
Zholos AV, Bolton TB. Muscarinic receptor subtypes controlling the cationic current in guinea-pig ileal smooth muscle. Br J Pharmacol, 1997, 122: 885–893
Pucovský V, Zholos AV, Bolton TB. Muscarinic cation current and suppression of Ca2+ current in guinea pig ileal smooth muscle cells. Eur J Pharmacol, 1998, 346: 323–330
Xu SZ, Zeng B, Daskoulidou N, Chen GL, Atkin SL, Lukhele B. Activation of TRPC cationic channels by mercurial compounds confers the cytotoxicity of mercury exposure. Toxicol Sci, 2012, 125: 56–68
Yoshida T, Inoue R, Morii T, Takahashi N, Yamamoto S, Hara Y, Tominaga M, Shimizu S, Sato Y, Mori Y. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat Chem Biol, 2006, 2: 596–607
Philipp S, Trost C, Warnat J, Rautmann J, Himmerkus N, Schroth G, Kretz O, Nastainczyk W, Cavalie A, Hoth M, Flockerzi V. TRP4 (CCE1) protein is part of native calcium release-activated Ca2+-like channels in adrenal cells. J Biol Chem, 2000, 275: 23965–23972
Wang X, Pluznick JL, Wei P, Padanilam BJ, Sansom SC. TRPC4 forms store-operated Ca2+ channels in mouse mesangial cells. Am J Physiol Cell Physiol, 2004, 287: C357–364
Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, Worley PF, Muallem S. TRPC channels as STIM1-regulated SOCs. Channels (Austin), 2009, 3: 221–225
Sours-Brothers S, Ding M, Graham S, Ma R. Interaction between TRPC1/TRPC4 assembly and STIM1 contributes to store-operated Ca2+ entry in mesangial cells. Exp Biol Med (Maywood), 2009, 234: 673–682
Cahalan MD, Zhang SL, Yeromin AV, Ohlsen K, Roos J, Stauderman KA. Molecular basis of the CRAC channel. Cell Calcium, 2007, 42: 133–144
Semtner M, Schaefer M, Pinkenburg O, Plant TD. Potentiation of TRPC5 by protons. J Biol Chem, 2007, 282: 33868–33878
Jung S, Muhle A, Schaefer M, Strotmann R, Schultz G, Plant TD. Lanthanides potentiate TRPC5 currents by an action at extracellular sites close to the pore mouth. J Biol Chem, 2003, 278: 3562–3571
Zhang L, Kolaj M, Renaud LP. GIRK-like and TRPC-like conductances mediate thyrotropin-releasing hormone-induced increases in excitability in thalamic paraventricular nucleus neurons. Neuropharmacology, 2013, 72: 106–115
Miller M, Shi J, Zhu Y, Kustov M, Tian JB, Stevens A, Wu M, Xu J, Long S, Yang P, Zholos AV, Salovich JM, Weaver CD, Hopkins CR, Lindsley CW, McManus O, Li M, Zhu MX. Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. J Biol Chem, 2011, 286: 33436–33446
Westlund KN, Zhang LP, Ma F, Nesemeier R, Ruiz JC, Ostertag EM, Crawford JS, Babinski K, Marcinkiewicz MM. A rat knockout model implicates TRPC4 in visceral pain sensation. Neuroscience, 2014, 262C: 165–175
Schaldecker T, Kim S, Tarabanis C, Tian D, Hakroush S, Castonguay P, Ahn W, Wallentin H, Heid H, Hopkins CR, Lindsley CW, Riccio A, Buvall L, Weins A, Greka A. Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest, 2013, 123: 5298–5309
Zhang L, Kolaj M and Renaud LP. GIRK-like and TRPC-like conductances mediate thyrotropin-releasing hormone-induced increases in excitability in thalamic paraventricular nucleus neurons. Neuropharmacology, 2013, 72: 106–115
Jiang H, Zeng B, Chen GL, Bot D, Eastmond S, Elsenussi SE, Atkin SL, Boa AN, Xu SZ. Effect of non-steroidal anti-inflammatory drugs and new fenamate analogues on TRPC4 and TRPC5 channels. Biochem Pharmacol, 2012, 83: 923–931
Xiong Q, Gao Z, Wang W, Li M. Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds. Trends Pharmacol Sci, 2008, 29: 99–107
Hu H, Tian J, Zhu Y, Wang C, Xiao R, Herz JM, Wood JD, Zhu MX. Activation of TRPA1 channels by fenamate nonsteroidal anti-inflammatory drugs. Pflugers Arch, 2009, 459: 579–592
Wimmers S, Strauss O. Basal calcium entry in retinal pigment epithelial cells is mediated by TRPC channels. Invest Ophthalmol Vis Sci, 2007, 48: 5767–5772
Singh A, Hildebrand ME, Garcia E, Snutch TP. The transient receptor potential channel antagonist SKF96365 is a potent blocker of low-voltage-activated T-type calcium channels. Br J Pharmacol, 2010, 160: 1464–1475
Xu SZ, Zeng F, Boulay G, Grimm C, Harteneck C, Beech DJ. Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Br J Pharmacol, 2005, 145: 405–414
Miehe S, Crause P, Schmidt T, Lohn M, Kleemann HW, Licher T, Dittrich W, Rutten H, Strubing C. Inhibition of diacylglycerol-sensitive TRPC channels by synthetic and natural steroids. PLoS One, 2012, 7:e35393
Zhang Z, Reboreda A, Alonso A, Barker P, Séguéla P. TRPC channels underlie cholinergic plateau potentials and persistent activity in entorhinal cortex. Hippocampus, 2011, 21: 386–397
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Fu, J., Gao, Z., Shen, B. et al. Canonical transient receptor potential 4 and its small molecule modulators. Sci. China Life Sci. 58, 39–47 (2015). https://doi.org/10.1007/s11427-014-4772-5
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DOI: https://doi.org/10.1007/s11427-014-4772-5