Review articleDifferent subcellular populations of L-type Ca2+ channels exhibit unique regulation and functional roles in cardiomyocytes
Highlights
► L-type Ca2+ channels regulate diverse cellular processes in the heart. ► Different L-type Ca2+ channel subpopulations exist in cardiomyocytes. ► Function and regulation of L-type Ca2+ channels depend on subcellular localization. ► Altered localization of L-type Ca2+ channels plays a role in heart disease.
Introduction
In the heart, voltage-dependent L-type Ca2+ channels (LTCCs) are essential to numerous cellular processes including excitability, excitation–contraction (EC) coupling, hormone secretion, and regulation of gene expression. Participation in such diverse functions demands that the influx of Ca2+ through L-type channels (L-type Ca2+ current, ICa,L) is tightly controlled and compartmentalized within the cardiac myocyte. It has long been recognized that discrete clusters of LTCCs exist along the sarcolemma, and studies in recent years have greatly extended our understanding of how specific subcellular localization impacts channel function and regulation by a variety of neurohormonal and second messenger pathways [1], [2], [3], [4], [5], [6].
A number of important LTCC subpopulations have been identified in cardiomyocytes that associate with unique macromolecular signaling complexes and scaffolding proteins, which enables spatiotemporal modulation of ICa,L. These include channels that are localized to dyadic junctions as well as extradyadic channels that reside in biochemically distinct regions of surface membrane known as membrane microdomains. Plasma membrane microdomains, including lipid rafts and caveolae, exhibit unique lipid composition and protein components and coordinate numerous cellular functions including various signal transduction pathways and protein recycling [7], [8], [9]. Numerous signaling molecules have been localized to caveolae including components of the β2-adrenergic receptor/adenylyl cyclase/protein kinase A (PKA) cascade [5], [6]. This review will highlight the evolving understanding of distinct subcellular populations of LTCCs in cardiomyocytes and their differing regulation and contributions to Ca2+ signaling in the heart.
Section snippets
Molecular composition of cardiac LTCCs
LTCCs are multimeric complexes consisting of a pore forming α1 subunit and auxiliary β, α2δ, and γ subunits [10]. The α1 subunit serves as the main functional component of the channel complex and consists of four homologous domains (I–IV) each containing six transmembrane segments (S1–S6). Cav1.2 (α1C, encoded by the CACNA1C gene) is the predominant α1 subunit in ventricular myocardium, whereas both Cav1.2 and Cav1.3 (α1D, encoded by CACNA1D) are expressed in atrial tissue as well as nodal
Subcellular localization impacts LTCC function
With each heart beat, ICa,L activates ryanodine receptors to release SR Ca2+ stores, leading to a transient rise in global [Ca2+]i from ~100 nM during diastole to ~ 1 μM during systole, which activates myofilament proteins, producing contraction. How then, is specificity of Ca2+ signaling achieved within the cardiomyocyte? It is increasingly recognized that the localization of LTCCs to structurally or biochemically distinct subcellular regions affords functional and physical compartmentalization.
Unique regulation of LTCC subpopulations
Neurohormonal regulation of LTCCs is central to the ability of the heart to adapt to changing physiological needs by altering heart rate and contractility [131], [132]. Membrane microdomains such as lipid rafts and caveolae are particularly well-suited for regulation of ICa,L because of the targeting of proteins involved in a variety of signaling cascades to these domains. Co-localization of signaling molecules with LTCCs enables highly localized and specific regulation of the channels.
Targeting LTCCs to subcellular compartments
Considering spatially defined subpopulations of LTCCs regulate discrete cellular functions, understanding the mechanisms responsible for appropriate channel targeting to various subcellular compartments in cardiac myocytes is important, yet these pathways are largely undefined. Recent advances in our understanding of LTCC trafficking in cardiomyocytes will be briefly discussed.
Altered microdomains disrupt LTCC function in cardiac disease
Dysregulation of LTCCs contributes to the pathophysiology of numerous heart diseases including heart failure, atrial fibrillation, and long and short QT syndromes [165], [166], [167], [168], [169], [170]. Several reports have suggested that the geometry and protein composition of subcellular compartments associated with LTCC activity are altered in some cardiac diseases [171], [172], [173], [174]. These changes could directly impact the function and regulation of LTCCs and contribute to defects
Conclusions and future directions
In cardiac myocytes, LTCCs are localized to multiple distinct subcellular compartments that impact their function and regulation (Fig. 2). The significance of dyadic LTCCs in EC coupling has long been recognized, but other subpopulations, such as those localized to caveolae, are increasingly implicated in a variety of cellular functions and signaling pathways. Many cardiac diseases involve changes in subcellular architecture and organization, thus altered subcellular localization of LTCCs with
Disclosures
None.
Acknowledgments
This work was supported by the National Heart, Lung, and Blood Institute Grant R01 HL078878 (to T.J.K.) and the American Heart Association Predoctoral Fellowship 10PRE2580002 (to J.M.B.).
References (201)
- et al.
Caveolae, ion channels and cardiac arrhythmias
Prog Biophys Mol Biol
(2008) Plasma membrane microdomains
Curr Opin Cell Biol
(2002)- et al.
Distribution, splicing and glucocorticoid-induced expression of cardiac alpha 1 C and alpha 1D voltage-gated Ca2+ channel mRNAs
J Mol Cell Cardiol
(1997) - et al.
Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels
Cell
(2000) - et al.
Expression and roles of Cav1.3 (α1D) L-type Ca2+ channel in atrioventricular node automaticity
J Mol Cell Cardiol
(2011) - et al.
L-type Ca2+ channel alpha 1c subunit isoform switching in failing human ventricular myocardium
J Mol Cell Cardiol
(2000) - et al.
Roles of a membrane-localized beta subunit in the formation and targeting of functional L-type Ca2+ channels
J Biol Chem
(1995) - et al.
Structural characterization of the dihydropyridine-sensitive calcium channel alpha 2-subunit and the associated delta peptides
J Biol Chem
(1991) - et al.
Molecular cloning of calcium channel alpha(2)delta-subunits from rat atria and the differential regulation of their expression by IGF-1
J Mol Cell Cardiol
(2003) - et al.
A family of gamma-like calcium channel subunits
FEBS Lett
(2000)