Review article
Different subcellular populations of L-type Ca2+ channels exhibit unique regulation and functional roles in cardiomyocytes

https://doi.org/10.1016/j.yjmcc.2011.08.014Get rights and content

Abstract

Influx of Ca2+ through L-type Ca2+ channels (LTCCs) contributes to numerous cellular processes in cardiomyocytes including excitation–contraction (EC) coupling, membrane excitability, and transcriptional regulation. Distinct subpopulations of LTCCs have been identified in cardiac myocytes, including those at dyadic junctions and within different plasma membrane microdomains such as lipid rafts and caveolae. These subpopulations of LTCCs exhibit regionally distinct functional properties and regulation, affording precise spatiotemporal modulation of L-type Ca2+ current (ICa,L). Different subcellular LTCC populations demonstrate variable rates of Ca2+-dependent inactivation and sometimes coupled gating of neighboring channels, which can lead to focal, persistent ICa,L. In addition, the assembly of spatially defined macromolecular signaling complexes permits compartmentalized regulation of ICa,L by a variety of neurohormonal pathways. For example, β-adrenergic receptor subtypes signal to different LTCC subpopulations, with β2-adrenergic activation leading to enhanced ICa,L through caveolar LTCCs and β1-adrenergic stimulation modulating LTCCs outside of caveolae. Disruptions in the normal subcellular targeting of LTCCs and associated signaling proteins may contribute to the pathophysiology of a variety of cardiac diseases including heart failure and certain arrhythmias. Further identifying the characteristic functional properties and array of regulatory molecules associated with specific LTCC subpopulations will provide a mechanistic framework to understand how LTCCs contribute to diverse cellular processes in normal and diseased myocardium. This article is part of a Special Issue entitled “Local Signaling in Myocytes”.

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.).

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