TRP Channels in the Heart

Calcium is an important second messenger in cardiac function. It is not only critical for the excitation-contraction coupling and relaxation of the heart (Bers, 2002), but it is also important for the activation of signal transduction pathways responsible for hypertrophic cardiac remodeling and heart failure, for example, by controlling gene transcription via Ca-dependent signaling as well as for cardiac development, cardiac energy homeostasis, and eventually for cell death (Frey et al., 2000; Frey et al., 2004; Roderick et al., 2007). In beating cardiomyocytes, fast cycling changes in cytosolic Ca concentration are the results of a timely coordinated interplay of voltage-gated Ca channels, sodium-calcium-exchangers, ryanodine receptors, and the SERCA-ATPase (Bers, 2008). However, the channels and pumps mediating the fast Ca cycling during beat-to-beat cardiac action are not only relevant for physiological cardiac functions but also for pathological processes such as development of pathological cardiac remodeling and development of heart failure. These pathological processes are essentially triggered by neuroendocrine stimuli such as noradrenaline, adrenaline, and angiotensin II, which subsequently lead to activation of G protein–dependent signaling pathways in cardiomyocytes that evoke Ca entry and Ca-dependent processes (e.g., activation of calcineurin/nuclear factor of activated T cells [NFAT], CaM-kinase, and protein kinase C inducing the development of myocyte growth and cardiac hypertrophy) (Heineke and Molkentin, 2006). Although the action of these sympathetic neurohormones represents an adaptive response that initially preserves cardiac function, the processes triggered by persistent activation during long-term cardiac stress leads to cardiac failure in many cardiovascular disease entities, including arterial hypertension and ischemic or valvular heart diseases. The sources of the Ca elevation and the mechanisms whereby Ca leads to calcineurin activation under repetitive Ca concentration changes during the contraction cycle are still not entirely understood. Sustained elevation of diastolic Ca levels has been identified as a mechanism (Dolmetsch et al., 1997) and can be achieved in cardiomyocytes (e.g., by an increase of Ca transient frequency to trigger remodeling processes) (Colella et al., 2008; Tavi et al., 2004). On the molecular level this can be due to alterations in Ca release from SR or Ca transport mechanisms across the plasma membrane with changes in the expression or function in the SERCA2, RyR2, IP receptor, sodium-calcium exchangers (NCX1), or Na/H exchanger (NHE1) (Goonasekera and Molkentin, 2012). The Ca entry pathways that are unrelated to those initiating contraction can evolve by targeting individual channels to subcellular microdomains such as caveolae, where a subset of L-type Ca channels are functional (Makarewich et al., 2012) and may colocalize with beta-adrenergic receptors outside the junctional ryanodine receptor/T-tubular complex (Balijepalli et al., 2006). The complexity of Ca-dependent regulation of cardiac hypertrophy by different molecular components becomes evident considering that even large increases of voltage-gated L-type Ca channels (LTCC) result in only mild cardiac hypertrophy (Beetz et al., 2009) and that reduced LTCC activity can also stimulate hypertrophy most likely via compensatory neuroendocrine stress leading to sensitized and leaky SR Ca release (Goonasekera and Molkentin, 2012). The concept of different Ca pools regulating contractility (“contractile Ca”) and remodeling (“signaling Ca”) arising from distinct spatial localization of Ca molecules is furthermore complicated by the developmental stage (neonatal/adult), the localization (atrial/ventricular), and the disease stage (nonfailing/failing) of the investigated cardiomyocytes. In addition to the pathways directly associated with fast Ca cycling, transient receptor potential (TRP) proteins have been uncovered in recent years as the molecular constituents of cation channels engaged by, for example, catecholamines or AngII in cardiac cells and as determinants of cardiac functions, although receptor- and store-operated Ca entry pathways were previously described in cardiac cells (Freichel et al., 1999). TRP proteins form Na- and Ca-conducting channels that can evoke changes in the Ca homeostasis beyond the time scale of beat-to-beat Ca transients and mediate longer-lasting modulation of Ca levels. The mammalian 28 TRP proteins are classified according to structural homology into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin). They are activated by numerous physical (e.g., mechanical stretch) and/or chemical stimuli (e.g., agonists including neurotransmitters) and can contribute to Ca homeostasis by directly conducting Ca or may contribute to Ca entry indirectly via membrane depolarization and modulation of voltage-gated Ca channels (Wu et al., 2010; Flockerzi and Nilius, 2014; Freichel et al., 2014). Thus, they have been proposed to be mediators of different physiological and pathophysiological cardiovascular processes (Inoue et al., 2006; Dietrich et al., 2007; Abramowitz and Birnbaumer, 2009; Watanabe et al., 2009; Dietrich et al., 2010; Vennekens, 2011). In the heart, initial attention has been placed to determine the role of TRP channels in the development of cardiac remodeling using and models (Guinamard and Bois, 2007; Nishida and Kurose, 2008; Eder and Molkentin, 2011). In this chapter we summarize the current knowledge regarding the expression and functional role of TRP channels for Ca homeostasis in cardiomyocytes and cardiac fibroblasts, their contribution to cardiac contractility and conduction, as well as the development of arrhythmias and pathological remodeling processes as determined by overexpression studies in cardiac cells/tissues, by knockdown/knockout of the corresponding genes, or by the use of specific channel inhibitors. Based on the increasing experimental evidence for their role in cardiac (dys)function derived from animal models and disease-associated mutations, individual TRP channels are becoming promising therapeutic targets for cardiac diseases.