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: 2.27). 10/2008; 98(2-3):149-60. DOI: 10.1016/j.pbiomolbio.2009.01.012
Source: PubMed


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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    • "In addition, depletion of membrane cholesterol increases the recruitment of Kv1.5 channels to the plasma membrane through Rab11-mediated channel recycling [51]. Lipid rafts and caveolae, two specialized membrane lipid structures, function as platforms for clustering of K þ channels and signaling molecules in macromolecular complexes , thereby modulating K þ channel properties [52] [53]. "
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    ABSTRACT: In the mammalian heart, multiple types of K(+) channels contribute to the control of cardiac electrical and mechanical functioning through the regulation of resting membrane potentials, action potential waveforms and refractoriness. There are similarly vast arrays of K(+) channel pore-forming and accessory subunits that contribute to the generation of functional myocardial K(+) channel diversity. Maladaptive remodeling of K(+) channels associated with cardiac and systemic diseases results in impaired repolarization and increased propensity for arrhythmias. Here, we review the diverse transcriptional, post-transcriptional, post-translational, and epigenetic mechanisms contributing to regulating the expression, distribution, and remodeling of cardiac K(+) channels under physiological and pathological conditions.
    Trends in cardiovascular medicine 09/2015; DOI:10.1016/j.tcm.2015.07.002 · 2.91 Impact Factor
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    • "Recent work suggests that caveolae play an important role in spatially restricting the response to β 2 -adrenergic stimulation [8] [9]. Caveolae are invaginations of the cell membrane, whose internal surface is lined with the scaffolding protein caveolin, caveolin-3 (Cav-3) being the prevalent form in adult cardiac myocytes [10]. Caveolin binds a variety of signaling molecules, including PKA, via a scaffolding domain to form signaling complexes and regulate their activity. "
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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 · 4.66 Impact Factor
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    • "The contact between PKC and Ca2+ channels was suggested to be required for generating constitutive Ca2+ influx [64]. This is consistent with the observation that a population of L-type Ca2+ channels is localized to caveolae in ventricular myocytes, since PKC was also predicted to reside in the same location [65] and has been reported for muscarinic smooth muscle [66]. It seems logical to propose that PKCα is anchored by caveolin- or caveolae-associated protein(s) to the cell membrane and activated by DAG there. "
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    ABSTRACT: Regulation of myosin light chain phosphatase (MLCP) via protein kinase C (PKC) and the 17 kDa PKC-potentiated inhibitor of myosin light chain phosphatase (CPI-17) has been reported as a Ca(2+) sensitization signaling pathway in smooth muscle (SM), and thus may be involved in tonic vs. phasic contractions. This study examined the protein expression and spatial-temporal distribution of PKCα and CPI-17 in intact SM tissues. KCl or carbachol (CCh) stimulation of tonic stomach fundus SM generates a sustained contraction while the phasic stomach antrum generates a transient contraction. In addition, the tonic fundus generates greater relative force than phasic antrum with 1 µM phorbol 12, 13-dibutyrate (PDBu) stimulation which is reported to activate the PKCα - CPI-17 pathway. Western blot analyses demonstrated that this contractile difference was not caused by a difference in the protein expression of PKCα or CPI-17 between these two tissues. Immunohistochemical results show that the distribution of PKCα in the longitudinal and circular layers of the fundus and antrum do not differ, being predominantly localized near the SM cell plasma membrane. Stimulation of either tissue with 1 µM PDBu or 1 µM CCh does not alter this peripheral PKCα distribution. There are no differences between these two tissues for the CPI-17 distribution, but unlike the PKCα distribution, CPI-17 appears to be diffusely distributed throughout the cytoplasm under relaxed tissue conditions but shifts to a primarily peripheral distribution at the plasma membrane with stimulation of the tissues with 1 µM PDBu or 1 µM CCh. Results from double labeling show that neither PKCα nor CPI-17 co-localize at the adherens junction (vinculin/talin) at the membrane but they do co-localize with each other and with caveoli (caveolin) at the membrane. This lack of difference suggests that the PKCα - CPI-17 pathway is not responsible for the tonic vs. phasic contractions observed in stomach fundus and antrum.
    PLoS ONE 09/2013; 8(9):e74608. DOI:10.1371/journal.pone.0074608 · 3.23 Impact Factor
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