TRP Channels in the Heart

Excerpt

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 Ca²⁺-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 Ca²⁺ concentration are the results of a timely coordinated interplay of voltage-gated Ca²⁺ channels, sodium-calcium-exchangers, ryanodine receptors, and the SERCA-ATPase (Bers, 2008). However, the channels and pumps mediating the fast Ca²⁺ 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 Ca²⁺ entry and Ca²⁺-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 Ca²⁺ elevation and the mechanisms whereby Ca²⁺ leads to calcineurin activation under repetitive Ca²⁺ concentration changes during the contraction cycle are still not entirely understood. Sustained elevation of diastolic Ca²⁺ levels has been identified as a mechanism (Dolmetsch et al., 1997) and can be achieved in cardiomyocytes (e.g., by an increase of Ca²⁺ 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 Ca²⁺ release from SR or Ca²⁺ transport mechanisms across the plasma membrane with changes in the expression or function in the SERCA2, RyR2, IP₃ receptor, sodium-calcium exchangers (NCX1), or Na⁺/H⁺ exchanger (NHE1) (Goonasekera and Molkentin, 2012). The Ca²⁺ 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 Ca²⁺ 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 Ca²⁺-dependent regulation of cardiac hypertrophy by different molecular components in vivo becomes evident considering that even large increases of voltage-gated L-type Ca²⁺ 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 Ca²⁺ release (Goonasekera and Molkentin, 2012). The concept of different Ca²⁺ pools regulating contractility (“contractile Ca²⁺”) and remodeling (“signaling Ca²⁺”) arising from distinct spatial localization of Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ entry pathways were previously described in cardiac cells (Freichel et al., 1999). TRP proteins form Na⁺- and Ca²⁺-conducting channels that can evoke changes in the Ca²⁺ homeostasis beyond the time scale of beat-to-beat Ca²⁺ transients and mediate longer-lasting modulation of Ca²⁺ 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 Ca²⁺ homeostasis by directly conducting Ca²⁺ or may contribute to Ca²⁺ entry indirectly via membrane depolarization and modulation of voltage-gated Ca²⁺ 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 in vitro and in vivo 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 Ca²⁺ 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.