Caveolae, ion channels and cardiac arrhythmias

Department of Medicine, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin, Madison, WI 53792, USA.
Progress in Biophysics and Molecular Biology (Impact Factor: 3.38). 10/2008; 98(2-3):149-60. DOI: 10.1016/j.pbiomolbio.2009.01.012
Source: PubMed

ABSTRACT Caveolae are specialized membrane microdomains enriched in cholesterol and sphingolipids which are present in multiple cell types including cardiomyocytes. Along with the essential scaffolding protein caveolin-3, a number of different ion channels and transporters have been localized to caveolae in cardiac myocytes including L-type Ca2+ channels (Ca(v)1.2), Na+ channels (Na(v)1.5), pacemaker channels (HCN4), Na+/Ca2+ exchanger (NCX1) and others. Closely associated with these channels are specific macromolecular signaling complexes that provide highly localized regulation of the channels. Mutations in the caveolin-3 gene (CAV3) have been linked with the congenital long QT syndrome (LQT9), and mutations in caveolar-localized ion channels may contribute to other inherited arrhythmias. Changes in the caveolar microdomain in acquired heart disease may also lead to dysregulation and dysfunction of ion channels, altering the risk of arrhythmias in conditions such as heart failure. This review highlights the existing evidence identifying and characterizing ion channels localized to caveolae in cardiomyocytes and their role in arrhythmogenesis.

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    ABSTRACT: L-type Ca channels (LTCC), which play a key role in cardiac excitation-contraction coupling, are located predominantly at the transverse (t-) tubules in ventricular myocytes. Caveolae and the protein caveolin-3 (Cav-3) are also present at the t-tubules and have been implicated in localizing a number of signaling molecules, including protein kinase A (PKA) and β2-adrenoreceptors. The present study investigated whether disruption of Cav-3 binding to its endogenous binding partners influenced LTCC activity. Ventricular myocytes were isolated from male Wistar rats and LTCC current (ICa) recorded using the whole-cell patch-clamp technique. Incubation of myocytes with a membrane-permeable peptide representing the scaffolding domain of Cav-3 (C3SD) reduced basal ICa amplitude in intact, but not detubulated, myocytes, and attenuated the stimulatory effects of the β2-adrenergic agonist zinterol on ICa. The PKA inhibitor H-89 also reduced basal ICa; however, the inhibitory effects of C3SD and H-89 on basal ICa amplitude were not summative. Under control conditions, myocytes stained with antibody against phosphorylated LTCC (pLTCC) displayed a striated pattern, presumably reflecting localization at the t-tubules. Both C3SD and H-89 reduced pLTCC staining at the z-lines but did not affect staining of total LTCC or Cav-3. These data are consistent with the idea that the effects of C3SD and H-89 share a common pathway, which involves PKA and is maximally inhibited by H-89, and suggest that Cav-3 plays an important role in mediating stimulation of ICa via PKA-induced phosphorylation under basal conditions, and in response to β2-adrenoceptor stimulation.
    Journal of Molecular and Cellular Cardiology 01/2014; 68(100). DOI:10.1016/j.yjmcc.2013.12.026 · 5.22 Impact Factor
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    ABSTRACT: Influx of Ca(2+) through L-type Ca(2+) 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 Ca(2+) current (I(Ca,L)). Different subcellular LTCC populations demonstrate variable rates of Ca(2+)-dependent inactivation and sometimes coupled gating of neighboring channels, which can lead to focal, persistent I(Ca,L). In addition, the assembly of spatially defined macromolecular signaling complexes permits compartmentalized regulation of I(Ca,L) by a variety of neurohormonal pathways. For example, β-adrenergic receptor subtypes signal to different LTCC subpopulations, with β(2)-adrenergic activation leading to enhanced I(Ca,L) through caveolar LTCCs and β(1)-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".
    Journal of Molecular and Cellular Cardiology 08/2011; 52(2):376-87. DOI:10.1016/j.yjmcc.2011.08.014 · 5.22 Impact Factor
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    ABSTRACT: It has recently been shown in epithelial cells that the ATP-gated ion channel P2X7R is in part, associated with caveolae and colocalized with caveolin-1. In the present study of the mouse heart, we show for the first time, using immunohistochemistry and cryoimmunoelectron microscopy, that P2X7R is expressed in atrial cardiomyocytes and in cardiac microvascular endothelial cells, but not in the ventricle cardiomyocytes. Furthermore, biochemical data indicate the presence of two forms of P2X7R, the classical glycosylated 80 kDa isoform and a protein with the molecular weight of 56 kDa, in both cardiomyocytes and endothelial cells of the mouse heart. The functionality of both proteins in heart cells is still unclear. In cardiac tissue homogenates derived from caveolin-1 deficient mice (cav-1(-/-)), an increase of the P2Xrx7 mRNA and P2X7R protein (80 kDa) was found, particularly in atrial samples. In addition, P2rx7(-/-) mice showed enhanced protein levels of caveolin-1 in their atrial tissues. Although the details of cellular mechanisms that underlie the relationship between caveolin-1 and P2X7R in atrial cardiomyocytes and the electrophysiological consequences of the increased P2X7R expression in atrial cells of cav-1(-/-) mice remain to be elucidated, the cardiomyopathy detectable in cav-1(-/-) mice is possibly related to a disturbed crosstalk between P2X7R and caveolin-1 in different heart cell populations.
    Histochemie 07/2010; 134(1):31-8. DOI:10.1007/s00418-010-0716-8 · 2.93 Impact Factor


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