Abstract
Transient receptor potential (TRP) channels are nonselective cationic channels that are generally Ca2+ permeable and have a heterogeneous expression in the heart. In the myocardium, TRP channels participate in several physiological functions, such as modulation of action potential waveform, pacemaking, conduction, inotropy, lusitropy, Ca2+ and Mg2+ handling, store-operated Ca2+ entry, embryonic development, mitochondrial function and adaptive remodelling. Moreover, TRP channels are also involved in various pathological mechanisms, such as arrhythmias, ischaemia–reperfusion injuries, Ca2+-handling defects, fibrosis, maladaptive remodelling, inherited cardiopathies and cell death. In this Review, we present the current knowledge of the roles of TRP channels in different cardiac regions (sinus node, atria, ventricles and Purkinje fibres) and cells types (cardiomyocytes and fibroblasts) and discuss their contribution to pathophysiological mechanisms, which will help to identify the best candidates for new therapeutic targets among the cardiac TRP family.
Key points
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Transient receptor potential (TRP) channels show heterogeneous expression between cardiac regions (sinus node, atria, Purkinje fibres and ventricles) and cell types (myocytes or fibroblasts).
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TRP channels are important in major physiological processes in the heart, such as regulation of Ca2+ homeostasis, contractility, pacemaking, conduction, modulation of the action potential, embryonic development and mitochondrial function.
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Cardiac pathologies are often associated with remodelling of TRP channel expression.
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TRP channel remodelling participates in the progression of cardiac diseases.
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Targeting TRP channels might be an interesting therapeutic strategy for cardiac pathologies.
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References
Montell, C. & Rubin, G. M. Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron 2, 1313–1323 (1989).
Madej, M. G. & Ziegler, C. M. Dawning of a new era in TRP channel structural biology by cryo-electron microscopy. Pflugers Arch. 470, 213–225 (2018).
Guo, J. et al. Structures of the calcium-activated, non-selective cation channel TRPM4. Nature 552, 205–209 (2017).
Yin, Y. et al. Structure of the cold- and menthol-sensing ion channel TRPM8. Science 359, 237–241 (2018).
Benemei, S., Patacchini, R., Trevisani, M. & Geppetti, P. TRP channels. Curr. Opin. Pharmacol. 22, 18–23 (2015).
Yue, Z. et al. Role of TRP channels in the cardiovascular system. Am. J. Physiol. Heart Circ. Physiol. 308, H157–H182 (2015).
Hofmann, L. et al. The S4–S5 linker — gearbox of TRP channel gating. Cell Calcium 67, 156–165 (2017).
Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).
Avila-Medina, J. et al. The complex role of store operated calcium entry pathways and related proteins in the function of cardiac, skeletal and vascular smooth muscle cells. Front. Physiol. 9, 257 (2018).
Vennekens, R. Recent insights on the role of TRP channels in cardiac muscle. Curr. Opin. Physiol. 1, 172–184 (2018).
Runnels, L. W. TRPM6 and TRPM7: a Mul-TRP-PLIK-cation of channel functions. Curr. Pharm. Biotechnol. 12, 42–53 (2011).
Du, J., Xie, J. & Yue, L. Intracellular calcium activates TRPM2 and its alternative spliced isoforms. Proc. Natl Acad. Sci. USA 106, 7239–7244 (2009).
Guinamard, R., Salle, L. & Simard, C. The non-selective monovalent cationic channels TRPM4 and TRPM5. Adv. Exp. Med. Biol. 704, 147–171 (2011).
Lakatta, E. G., Maltsev, V. A. & Vinogradova, T. M. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart’s pacemaker. Circ. Res. 106, 659–673 (2010).
Yanni, J. et al. Changes in ion channel gene expression underlying heart failure-induced sinoatrial node dysfunction. Circ. Heart Fail. 4, 496–508 (2011).
Ju, Y. K. et al. Store-operated Ca2+ influx and expression of TRPC genes in mouse sinoatrial node. Circ. Res. 100, 1605–1614 (2007).
Sabourin, J., Robin, E. & Raddatz, E. A key role of TRPC channels in the regulation of electromechanical activity of the developing heart. Cardiovasc. Res. 92, 226–236 (2011).
Ju, Y. K. et al. The involvement of TRPC3 channels in sinoatrial arrhythmias. Front. Physiol. 6, 86 (2015).
Hofmann, T. et al. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397, 259–263 (1999).
Doleschal, B. et al. TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1. Cardiovasc. Res. 106, 163–173 (2015).
Qi, Z. et al. TRPC3 regulates the automaticity of embryonic stem cell-derived cardiomyocytes. Int. J. Cardiol. 203, 169–181 (2016).
Demion, M., Bois, P., Launay, P. & Guinamard, R. TRPM4, a Ca2+-activated nonselective cation channel in mouse sino-atrial node cells. Cardiovasc. Res. 73, 531–538 (2007).
Sasse, P. et al. Intracellular Ca2+ oscillations, a potential pacemaking mechanism in early embryonic heart cells. J. Gen. Physiol. 130, 133–144 (2007).
Guo, J., Ono, K. & Noma, A. Monovalent cation conductance of the sustained inward current in rabbit sinoatrial node cells. Pflugers Arch. 433, 209–211 (1996).
Guinamard, R., Hof, T. & Del Negro, C. A. The TRPM4 channel inhibitor 9-phenanthrol. Br. J. Pharmacol. 171, 1600–1613 (2014).
Hof, T., Simard, C., Rouet, R., Salle, L. & Guinamard, R. Implication of the TRPM4 nonselective cation channel in mammalian sinus rhythm. Heart Rhythm 10, 1683–1689 (2013).
Hu, Y. et al. Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches. Cardiovasc. Res. 113, 1243–1255 (2017).
DiFrancesco, D. The role of the funny current in pacemaker activity. Circ. Res. 106, 434–446 (2010).
Sah, R. et al. Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity. Proc. Natl Acad. Sci. USA 110, E3037–E3046 (2013).
Zhang, Y. H. et al. Functional transient receptor potential canonical type 1 channels in human atrial myocytes. Pflugers Arch. 465, 1439–1449 (2013).
Guinamard, R. et al. Functional characterization of a Ca2+-activated non-selective cation channel in human atrial cardiomyocytes. J. Physiol. 558, 75–83 (2004).
Zhang, Y. H. et al. Evidence for functional expression of TRPM7 channels in human atrial myocytes. Basic Res. Cardiol. 107, 282 (2012).
Macianskiene, R., Almanaityte, M., Jekabsone, A. & Mubagwa, K. Modulation of human cardiac TRPM7 current by extracellular acidic pH depends upon extracellular concentrations of divalent cations. PLOS ONE 12, e0170923 (2017).
Simard, C., Hof, T., Keddache, Z., Launay, P. & Guinamard, R. The TRPM4 non-selective cation channel contributes to the mammalian atrial action potential. J. Mol. Cell. Cardiol. 59, 11–19 (2013).
Demion, M. et al. Trpm4 gene invalidation leads to cardiac hypertrophy and electrophysiological alterations. PLOS ONE 9, e115256 (2014).
Guinamard, R. et al. TRPM4 in cardiac electrical activity. Cardiovasc. Res. 108, 21–30 (2015).
Odnoshivkina, U. G. et al. β2-adrenoceptor agonist-evoked reactive oxygen species generation in mouse atria: implication in delayed inotropic effect. Eur. J. Pharmacol. 765, 140–153 (2015).
Chevalier, M. et al. Transcriptomic analyses of murine ventricular cardiomyocytes. Sci. Data 5, 180170 (2018).
Pazienza, V. et al. The TRPA1 channel is a cardiac target of mIGF-1/SIRT1 signaling. Am. J. Physiol. Heart Circ. Physiol. 307, H939–H944 (2014).
Lu, Y., Piplani, H., McAllister, S. L., Hurt, C. M. & Gross, E. R. Transient receptor potential ankyrin 1 activation within the cardiac myocyte limits ischemia-reperfusion injury in rodents. Anesthesiology 125, 1171–1180 (2016).
Andrei, S. R., Sinharoy, P., Bratz, I. N. & Damron, D. S. TRPA1 is functionally co-expressed with TRPV1 in cardiac muscle: co-localization at Z-discs, costameres and intercalated discs. Channels 10, 395–409 (2016).
Bodkin, J. V. et al. Investigating the potential role of TRPA1 in locomotion and cardiovascular control during hypertension. Pharmacol. Res. Perspect. 2, e00052 (2014).
Andrei, S. R. et al. TRPA1 ion channel stimulation enhances cardiomyocyte contractile function via a CaMKII-dependent pathway. Channels 11, 587–603 (2017).
Camacho Londono, J. E. et al. A background Ca2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling. Eur. Heart J. 36, 2257–2266 (2015).
Miller, B. A. et al. The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 304, H1010–H1022 (2013).
Hoffman, N. E. et al. Ca2+ entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. Am. J. Physiol. Heart Circ. Physiol. 308, H637–H650 (2015).
Hof, T. et al. TRPM4 non-selective cation channels influence action potentials in rabbit Purkinje fibres. J. Physiol. 594, 295–306 (2016).
Guinamard, R., Demion, M., Magaud, C., Potreau, D. & Bois, P. Functional expression of the TRPM4 cationic current in ventricular cardiomyocytes from spontaneously hypertensive rats. Hypertension 48, 587–594 (2006).
Guinamard, R., Rahmati, M., Lenfant, J. & Bois, P. Characterization of a Ca2+-activated nonselective cation channel during dedifferentiation of cultured rat ventricular cardiomyocytes. J. Membr. Biol. 188, 127–135 (2002).
Mathar, I. et al. Increased beta-adrenergic inotropy in ventricular myocardium from Trpm4 −/− mice. Circ. Res. 114, 283–294 (2014).
Gueffier, M. et al. The TRPM4 channel is functionally important for the beneficial cardiac remodeling induced by endurance training. J. Muscle Res. Cell. Motil. 38, 3–16 (2017).
Kecskes, M. et al. The Ca2+-activated cation channel TRPM4 is a negative regulator of angiotensin II-induced cardiac hypertrophy. Basic Res. Cardiol. 110, 43 (2015).
Saito, Y. et al. TRPM4 mutation in patients with ventricular noncompaction and cardiac conduction disease. Circ. Genom. Precis. Med. 11, e002103 (2018).
Gwanyanya, A., Sipido, K. R., Vereecke, J. & Mubagwa, K. ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes. Am. J. Physiol. Cell. Physiol. 291, C627–C635 (2006).
Sah, R. et al. Timing of myocardial Trpm7 deletion during cardiogenesis variably disrupts adult ventricular function, conduction, and repolarization. Circulation 128, 101–114 (2013).
Rubinstein, J. et al. Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance. Am. J. Physiol. Heart Circ. Physiol. 306, H574–H584 (2014).
Aguettaz, E. et al. Axial stretch-dependent cation entry in dystrophic cardiomyopathy: involvement of several TRPs channels. Cell Calcium 59, 145–155 (2016).
Aguettaz, E., Bois, P., Cognard, C. & Sebille, S. Stretch-activated TRPV2 channels: role in mediating cardiopathies. Prog. Biophys. Mol. Biol. 130, 273–280 (2017).
Katanosaka, Y. et al. TRPV2 is critical for the maintenance of cardiac structure and function in mice. Nat. Commun. 5, 3932 (2014).
Zhao, Y. et al. Unusual localization and translocation of TRPV4 protein in cultured ventricular myocytes of the neonatal rat. Eur. J. Histochem. 56, e32 (2012).
Hu, L., Ma, J., Zhang, P. & Zheng, J. Extracellular hypotonicity induces disturbance of sodium currents in rat ventricular myocytes. Physiol. Res. 58, 807–815 (2009).
Li, J. et al. Role of transient receptor potential vanilloid 4 in the effect of osmotic pressure on myocardial contractility in rat. Sheng Li Xue Bao 60, 181–188 (2008).
Heckel, E. et al. Oscillatory flow modulates mechanosensitive klf2a expression through trpv4 and trpp2 during heart valve development. Curr. Biol. 25, 1354–1361 (2015).
Fick, G. M., Johnson, A. M., Hammond, W. S. & Gabow, P. A. Causes of death in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 5, 2048–2056 (1995).
Paavola, J. et al. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J. Mol. Cell. Cardiol. 58, 199–208 (2013).
Volk, T., Schwoerer, A. P., Thiessen, S., Schultz, J. H. & Ehmke, H. A polycystin-2-like large conductance cation channel in rat left ventricular myocytes. Cardiovasc. Res. 58, 76–88 (2003).
Anyatonwu, G. I., Estrada, M., Tian, X., Somlo, S. & Ehrlich, B. E. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc. Natl Acad. Sci. USA 104, 6454–6459 (2007).
Kuo, I. Y. et al. Decreased polycystin 2 expression alters calcium-contraction coupling and changes beta-adrenergic signaling pathways. Proc. Natl Acad. Sci. USA 111, 16604–16609 (2014).
Haissaguerre, M., Vigmond, E., Stuyvers, B., Hocini, M. & Bernus, O. Ventricular arrhythmias and the His-Purkinje system. Nat. Rev. Cardiol. 13, 155–166 (2016).
Hirose, M., Stuyvers, B. D., Dun, W., ter Keurs, H. E. & Boyden, P. A. Function of Ca2+ release channels in Purkinje cells that survive in the infarcted canine heart: a mechanism for triggered Purkinje ectopy. Circ. Arrhythm. Electrophysiol. 1, 387–395 (2008).
Huang, H. et al. TRPC1 expression and distribution in rat hearts. Eur. J. Histochem. 53, e26 (2009).
Liu, H. et al. Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease. Circ. Cardiovasc. Genet. 3, 374–385 (2010).
Kruse, M. et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J. Clin. Invest. 119, 2737–2744 (2009).
Lighthouse, J. K. & Small, E. M. Transcriptional control of cardiac fibroblast plasticity. J. Mol. Cell. Cardiol. 91, 52–60 (2016).
Thodeti, C. K., Paruchuri, S. & Meszaros, J. G. A. TRP to cardiac fibroblast differentiation. Channels 7, 211–214 (2013).
Hinz, B. Formation and function of the myofibroblast during tissue repair. J. Invest. Dermatol. 127, 526–537 (2007).
Davis, J., Burr, A. R., Davis, G. F., Birnbaumer, L. & Molkentin, J. D. A. TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev. Cell 23, 705–715 (2012).
Nattel, S. & Dobrev, D. The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. Eur. Heart J. 33, 1870–1877 (2012).
Nattel, S. & Dobrev, D. Electrophysiological and molecular mechanisms of paroxysmal atrial fibrillation. Nat. Rev. Cardiol. 13, 575–590 (2016).
Macianskiene, R., Martisiene, I., Zablockaite, D. & Gendviliene, V. Characterization of Mg2+-regulated TRPM7-like current in human atrial myocytes. J. Biomed. Sci. 19, 75 (2012).
Ohba, T. et al. Upregulation of TRPC1 in the development of cardiac hypertrophy. J. Mol. Cell. Cardiol. 42, 498–507 (2007).
Han, J. W. et al. Resistance to pathologic cardiac hypertrophy and reduced expression of CaV1.2 in Trpc3-depleted mice. Mol. Cell. Biochem. 421, 55–65 (2016).
Seo, K. et al. Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy. Proc. Natl Acad. Sci. USA 111, 1551–1556 (2014).
Swaminathan, P. D., Purohit, A., Hund, T. J. & Anderson, M. E. Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias. Circ. Res. 110, 1661–1677 (2012).
Bush, E. W. et al. Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling. J. Biol. Chem. 281, 33487–33496 (2006).
Oguri, G. et al. Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels. Am. J. Physiol. Heart Circ. Physiol. 307, H1339–H1352 (2014).
Adapala, R. K. et al. TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals. J. Mol. Cell. Cardiol. 54, 45–52 (2013).
Wu, X., Eder, P., Chang, B. & Molkentin, J. D. TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc. Natl Acad. Sci. USA 107, 7000–7005 (2010).
Goel, M., Zuo, C. D., Sinkins, W. G. & Schilling, W. P. TRPC3 channels colocalize with Na+/Ca2+ exchanger and Na+ pump in axial component of transverse-axial tubular system of rat ventricle. Am. J. Physiol. Heart Circ. Physiol. 292, H874–H883 (2007).
Kitajima, N. et al. TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts. Biochem. Biophys. Res. Commun. 409, 108–113 (2011).
Wagner, S. et al. NADPH oxidase 2 mediates angiotensin II-dependent cellular arrhythmias via PKA and CaMKII. J. Mol. Cell. Cardiol. 75, 206–215 (2014).
Morine, K. J. et al. Endoglin selectively modulates transient receptor potential channel expression in left and right heart failure. Cardiovasc. Pathol. 25, 478–482 (2016).
Ohba, T. et al. Regulatory role of neuron-restrictive silencing factor in expression of TRPC1. Biochem. Biophys. Res. Commun. 351, 764–770 (2006).
Nakayama, H., Wilkin, B. J., Bodi, I. & Molkentin, J. D. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J. 20, 1660–1670 (2006).
Brenner, J. S. & Dolmetsch, R. E. TrpC3 regulates hypertrophy-associated gene expression without affecting myocyte beating or cell size. PLOS ONE 2, e802 (2007).
Koitabashi, N. et al. Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation: novel mechanism of cardiac stress modulation by PDE5 inhibition. J. Mol. Cell. Cardiol. 48, 713–724 (2010).
Onohara, N. et al. TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J. 25, 5305–5316 (2006).
Kuwahara, K. et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J. Clin. Invest. 116, 3114–3126 (2006).
Koch, S. E. et al. Transient receptor potential vanilloid 2 function regulates cardiac hypertrophy via stretch-induced activation. J. Hypertens. 35, 602–611 (2017).
Miller, B. A. et al. TRPM2 channels protect against cardiac ischemia-reperfusion injury: role of mitochondria. J. Biol. Chem. 289, 7615–7629 (2014).
Jacobs, G. et al. Enhanced β-adrenergic cardiac reserve in Trpm4 -/- mice with ischaemic heart failure. Cardiovasc. Res. 105, 330–339 (2015).
Wang, J., Takahashi, K., Piao, H., Qu, P. & Naruse, K. 9-Phenanthrol, a TRPM4 inhibitor, protects isolated rat hearts from ischemia-reperfusion injury. PLOS ONE 8, e70587 (2013).
Piao, H. et al. Transient receptor potential melastatin-4 is involved in hypoxia-reoxygenation injury in the cardiomyocytes. PLOS ONE 10, e0121703 (2015).
Simard, C., Salle, L., Rouet, R. & Guinamard, R. Transient receptor potential melastatin 4 inhibitor 9-phenanthrol abolishes arrhythmias induced by hypoxia and re-oxygenation in mouse ventricle. Br. J. Pharmacol. 165, 2354–2364 (2012).
Nilius, B., Prenen, J., Voets, T. & Droogmans, G. Intracellular nucleotides and polyamines inhibit the Ca2+-activated cation channel TRPM4b. Pflugers Arch. 448, 70–75 (2004).
Carmeliet, E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol. Rev. 79, 917–1017 (1999).
Ortega, A. et al. TRPM7 is down-regulated in both left atria and left ventricle of ischaemic cardiomyopathy patients and highly related to changes in ventricular function. ESC Heart Fail. 3, 220–224 (2016).
Vemula, P., Gautam, B., Abela, G. S. & Wang, D. H. Myocardial ischemia/reperfusion injury: potential of TRPV1 agonists as cardioprotective agents. Cardiovasc. Hematol. Disord. Drug Targets 14, 71–78 (2014).
Randhawa, P. K. & Jaggi, A. S. TRPV1 and TRPV4 channels: potential therapeutic targets for ischemic conditioning-induced cardioprotection. Eur. J. Pharmacol. 746, 180–185 (2015).
Wang, L. & Wang, D. H. TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation 112, 3617–3623 (2005).
Huang, W., Rubinstein, J., Prieto, A. R., Thang, L. V. & Wang, D. H. Transient receptor potential vanilloid gene deletion exacerbates inflammation and atypical cardiac remodeling after myocardial infarction. Hypertension 53, 243–250 (2009).
Dong, Q. et al. Blockage of transient receptor potential vanilloid 4 alleviates myocardial ischemia/reperfusion injury in mice. Sci. Rep. 7, 42678 (2017).
Syam, N. et al. Variants of transient receptor potential melastatin member 4 in childhood atrioventricular block. J. Am. Heart Assoc. 5, e001625 (2016).
Liu, H. et al. Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel. PLOS ONE 8, e54131 (2013).
Hof, T. et al. TRPM4 non-selective cation channel variants in long QT syndrome. BMC Med. Genet. 18, 31 (2017).
Xian, W. et al. Aberrant deactivation-induced gain of function in TRPM4 mutant is associated with human cardiac conduction block. Cell Rep. 24, 724–731 (2018).
Arking, D. E. et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat. Genet. 46, 826–836 (2014).
Eder, P. et al. Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex. Cardiovasc. Res. 73, 111–119 (2007).
Kitajima, N. et al. TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling. Sci. Rep. 6, 37001 (2016).
Yue, Z., Zhang, Y., Xie, J., Jiang, J. & Yue, L. Transient receptor potential (TRP) channels and cardiac fibrosis. Curr. Top. Med. Chem. 13, 270–282 (2013).
Numaga-Tomita, T. et al. TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. Sci. Rep. 6, 39383 (2016).
Oda, S. et al. TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice. Sci. Rep. 7, 7511 (2017).
Ikeda, K. et al. Roles of transient receptor potential canonical (TRPC) channels and reverse-mode Na+/Ca2+ exchanger on cell proliferation in human cardiac fibroblasts: effects of transforming growth factor β1. Cell Calcium 54, 213–225 (2013).
Harada, M. et al. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation 126, 2051–2064 (2012).
Hatano, N., Itoh, Y. & Muraki, K. Cardiac fibroblasts have functional TRPV4 activated by 4α-phorbol 12,13-didecanoate. Life Sci. 85, 808–814 (2009).
Du, J. et al. TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circ. Res. 106, 992–1003 (2010).
Nakatani, Y. et al. Tranilast prevents atrial remodeling and development of atrial fibrillation in a canine model of atrial tachycardia and left ventricular dysfunction. J. Am. Coll. Cardiol. 61, 582–588 (2013).
Guo, J. L. et al. Transient receptor potential melastatin 7 (TRPM7) contributes to H2O2-induced cardiac fibrosis via mediating Ca2+ influx and extracellular signal-regulated kinase 1/2 (ERK1/2) activation in cardiac fibroblasts. J. Pharmacol. Sci. 125, 184–192 (2014).
Yu, Y. et al. TRPM7 is involved in angiotensin II induced cardiac fibrosis development by mediating calcium and magnesium influx. Cell Calcium 55, 252–260 (2014).
Li, S. et al. TRPM7 channels mediate the functional changes in cardiac fibroblasts induced by angiotensin II. Int. J. Mol. Med. 39, 1291–1298 (2017).
Shimauchi, T. et al. TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy. JCI Insight 2, e93358 (2017).
Ozhathil, L. C. et al. Identification of potent and selective small molecule inhibitors of the cation channel TRPM4. Br. J. Pharmacol. 175, 2504–2519 (2018).
Rubaiy, H. N. et al. Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels. J. Biol. Chem. 292, 8158–8173 (2017).
Koch, S. E. et al. Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation. J. Mol. Cell. Cardiol. 53, 134–144 (2012).
Iwata, Y. et al. Blockade of sarcolemmal TRPV2 accumulation inhibits progression of dilated cardiomyopathy. Cardiovasc. Res. 99, 760–768 (2013).
Matsumura, T. et al. A pilot study of tranilast for cardiomyopathy of muscular dystrophy. Intern. Med. 57, 311–318 (2018).
Sheth, K. N. et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 15, 1160–1169 (2016).
Okada, T. et al. Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca2+-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptor. J. Biol. Chem. 274, 27359–27370 (1999).
Bobkov, Y. V., Corey, E. A. & Ache, B. W. The pore properties of human nociceptor channel TRPA1 evaluated in single channel recordings. Biochim. Biophys. Acta 1808, 1120–1128 (2011).
Gees, M., Colsoul, B. & Nilius, B. The role of transient receptor potential cation channels in Ca2+ signaling. Cold Spring Harb. Perspect. Biol. 2, a003962 (2010).
Dominguez-Rodriguez, A. et al. Proarrhythmic effect of sustained EPAC activation on TRPC3/4 in rat ventricular cardiomyocytes. J. Mol. Cell. Cardiol. 87, 74–78 (2015).
Wang, Y., Chen, M. S., Liu, H. C., Xiao, J. H. & Wang, J. L. The relationship between frequency dependence of action potential duration and the expression of TRPC3 in rabbit ventricular myocardium. Cell Physiol. Biochem. 33, 646–656 (2014).
Dyachenko, V., Husse, B., Rueckschloss, U. & Isenberg, G. Mechanical deformation of ventricular myocytes modulates both TRPC6 and Kir2.3 channels. Cell Calcium 45, 38–54 (2009).
Xie, J. et al. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat. Commun. 3, 1238 (2012).
Demir, T. et al. Evaluation of TRPM (transient receptor potential melastatin) genes expressions in myocardial ischemia and reperfusion. Mol. Biol. Rep. 41, 2845–2849 (2014).
Takahashi, K., Sakamoto, K. & Kimura, J. Hypoxic stress induces transient receptor potential melastatin 2 (TRPM2) channel expression in adult rat cardiac fibroblasts. J. Pharmacol. Sci. 118, 186–197 (2012).
Kuster, D. W. et al. MicroRNA transcriptome profiling in cardiac tissue of hypertrophic cardiomyopathy patients with MYBPC3 mutations. J. Mol. Cell. Cardiol. 65, 59–66 (2013).
Zhainazarov, A. B. Ca2+-activated nonselective cation channels in rat neonatal atrial myocytes. J. Membr. Biol. 193, 91–98 (2003).
Fonfria, E. et al. Tissue distribution profiles of the human TRPM cation channel family. J. Recept. Signal Transduct. Res. 26, 159–178 (2006).
Rose, R. A., Hatano, N., Ohya, S., Imaizumi, Y. & Giles, W. R. C-type natriuretic peptide activates a non-selective cation current in acutely isolated rat cardiac fibroblasts via natriuretic peptide C receptor-mediated signalling. J. Physiol. 580, 255–274 (2007).
Zhou, Y., Yi, X., Wang, T. & Li, M. Effects of angiotensin II on transient receptor potential melastatin 7 channel function in cardiac fibroblasts. Exp. Ther. Med. 9, 2008–2012 (2015).
Giehl, E. et al. Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress. Pflugers Arch. 469, 1507–1517 (2017).
Basora, N. et al. Tissue and cellular localization of a novel polycystic kidney disease-like gene product, polycystin-L. J. Am. Soc. Nephrol. 13, 293–301 (2002).
Dvorakova, M. & Kummer, W. Transient expression of vanilloid receptor subtype 1 in rat cardiomyocytes during development. Histochem. Cell Biol. 116, 223–225 (2001).
Zhong, B. & Wang, D. H. Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: role of transient receptor potential vanilloid receptors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R1681–R1690 (2009).
Gao, F. et al. TRPV1 activation attenuates high-salt diet-induced cardiac hypertrophy and fibrosis through PPAR-δ upregulation. PPAR Res. 2014, 491963 (2014).
Sexton, A., McDonald, M., Cayla, C., Thiemermann, C. & Ahluwalia, A. 12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1. FASEB J. 21, 2695–2703 (2007).
Buckley, C. L. & Stokes, A. J. Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy. Channels 5, 367–374 (2011).
Horton, J. S., Buckley, C. L. & Stokes, A. J. Successful TRPV1 antagonist treatment for cardiac hypertrophy and heart failure in mice. Channels 7, 17–22 (2013).
Lang, H. et al. Activation of TRPV1 attenuates high salt-induced cardiac hypertrophy through improvement of mitochondrial function. Br. J. Pharmacol. 172, 5548–5558 (2015).
Wu, Q. F. et al. Activation of transient receptor potential vanilloid 4 involves in hypoxia/reoxygenation injury in cardiomyocytes. Cell Death Dis. 8, e2828 (2017).
Ohba, T. et al. Stromal interaction molecule 1 haploinsufficiency causes maladaptive response to pressure overload. PLOS ONE 12, e0187950 (2017).
Satoh, S. et al. Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca2+ channel mediating angiotensin II-induced myocardial apoptosis. Mol. Cell. Biochem. 294, 205–215 (2007).
Iwata, Y. et al. A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel. J. Cell Biol. 161, 957–967 (2003).
Acknowledgements
L.S. and R.G. are supported by a grant from “Région Normandie”. The authors acknowledge R. Coronel (IHU-Liryc, Bordeaux Université, France, and Academic Medical Center, University of Amsterdam, Netherlands) for helpful advice and R. Walton (IHU-Liryc, Bordeaux Université, France) for English editing of the manuscript.
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Nature Reviews Cardiology thanks M. Nishida and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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T.H., S.C. and R.G. wrote the manuscript, and all authors researched data for the article, discussed its content and reviewed and edited it before submission.
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Hof, T., Chaigne, S., Récalde, A. et al. Transient receptor potential channels in cardiac health and disease. Nat Rev Cardiol 16, 344–360 (2019). https://doi.org/10.1038/s41569-018-0145-2
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DOI: https://doi.org/10.1038/s41569-018-0145-2
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