In-vivo phosphorylation of the cardiac L-type calcium channel beta-subunit in response to catecholamines

Haase, Hannelore; Bartel, Sabine; Karczewski, Peter; Morano, Ingo; Krause, Ernst

doi:10.1007/bf00408645

Cited by 60 publications

(19 citation statements)

References 36 publications

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“…Ca V β 2 is phosphorylated both in vitro by PKA-CS on Ser459, Ser478, Ser479, and Ser296 (numbering by rabbit β 2b ) and in vivo after adrenergic stimulation. [77][78][79][80] In summary, these studies satisfied criteria 3 and 5: α 1C and β subunits of Ca V 1.2 are PKA targets; the functional importance of the various phosphorylation sites is discussed below.…”

Section: Both α 1c and β Subunits Are Phosphorylated By Pkamentioning

confidence: 89%

Regulation of Cardiac L-Type Ca ²⁺ Channel Ca _V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

Weiss

Benmocha

et al. 2013

Circulation Research

101

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Abstract:In the heart, adrenergic stimulation activates the β-adrenergic receptors coupled to the heterotrimeric stimulatory G s protein, followed by subsequent activation of adenylyl cyclase, elevation of cyclic AMP levels, and protein kinase A (PKA) activation. One of the main targets for PKA modulation is the cardiac L-type Ca 2+ channel (Ca V 1.2) located in the plasma membrane and along the T-tubules, which mediates Ca 2+ entry into cardiomyocytes. β-Adrenergic receptor activation increases the Ca 2+ current via Ca V 1.2 channels and is responsible for the positive ionotropic effect of adrenergic stimulation. Despite decades of research, the molecular mechanism underlying this modulation has not been fully resolved. On the contrary, initial reports of identification of key components in this modulation were later refuted using advanced model systems, especially transgenic animals. Some of the cardinal debated issues include details of specific subunits and residues in Ca

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Section: Both α 1c and β Subunits Are Phosphorylated By Pkamentioning

confidence: 89%

Regulation of Cardiac L-Type Ca ²⁺ Channel Ca _V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

Weiss

Benmocha

et al. 2013

Circulation Research

101

View full text Add to dashboard Cite

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“…Despite decades of research on the regulation of voltage-gated ion channels by protein phosphorylation, few phosphorylation events that alter ion channel activity have been shown to be physiologically modulated in vivo (43)(44)(45). This is especially true of the positive feedback regulation of L-type and T-type channels by CaMKII.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II

Yao¹

2006

Journal of Clinical Investigation

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“…13,64 Application of the ␤AR agonist isoproterenol in vivo resulted in phosphorylation of 1 or more PKA sites of the cardiac L-type channel ␤ subunits. 66,67 PKA phosphorylates 3 sites of ␤ 2a (Ser459, Ser478, and Ser479) in vitro ( Figure 1). 68 To test the functional relevance of these phosphorylation sites, ␤ 2a was coexpressed with a C-terminally truncated version of ␣ 1C that lacks Ser1928.…”

Section: Biochemical and Functional Characterization Of Channel Phospmentioning

confidence: 99%

Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C

Kamp

Hell

2000

Circulation Research

546

421

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Abstract-Voltage-dependent L-type Ca 2ϩ channels are multisubunit transmembrane proteins, which allow the influx of Ca 2ϩ (I Ca ) essential for normal excitability and excitation-contraction coupling in cardiac myocytes. A variety of different receptors and signaling pathways provide dynamic regulation of I Ca in the intact heart. The present review focuses on recent evidence describing the molecular details of regulation of L-type Ca 2ϩ channels by protein kinase A (PKA) and protein kinase C (PKC) pathways. Multiple G protein-coupled receptors act through cAMP/PKA pathways to regulate L-type channels. ␤-Adrenergic receptor stimulation results in a marked increase in I Ca , which is mediated by a cAMP/PKA pathway. Growing evidence points to an important role of localized signaling complexes involved in the PKA-mediated regulation of I Ca , including A-kinase anchor proteins and binding of phosphatase PP2a to the carboxyl terminus of the ␣ 1C (Ca v 1.2) subunit. Both ␣ 1C and ␤ 2a subunits of the channel are substrates for PKA in vivo. The regulation of L-type Ca 2ϩ channels by Gq-linked receptors and associated PKC activation is complex, with both stimulation and inhibition of I Ca being observed. The amino terminus of the ␣ 1C subunit is critically involved in PKC regulation. Crosstalk between PKA and PKC pathways occurs in the modulation of I Ca . Ultimately, precise regulation of I Ca is needed for normal cardiac function, and alterations in these regulatory pathways may prove important in heart disease. (Circ Res. 2000;87:1095-1102.)Key Words: L-type calcium channel Ⅲ protein kinase C Ⅲ protein kinase A Ⅲ heart Ⅲ regulation Ⅲ phosphorylation T he influx of Ca 2ϩ ions through voltage-dependent L-type Ca 2ϩ channels plays an essential role in cardiac excitability and in coupling excitation to contraction. The depolarizing current through L-type Ca 2ϩ channels (I Ca ) contributes to the plateau phase of the cardiac action potential as well as to pacemaker activity in nodal cells. This influx of Ca 2ϩ triggers the release of intracellular stores of Ca 2ϩ from the sarcoplasmic reticulum, and the ensuing intracellular Ca 2ϩ transient results in activation of the myofilaments. L-type channels can also impact on other cellular processes modulated by intracellular Ca 2ϩ such as gene expression and excitation-secretion coupling. Alterations in density or function of L-type Ca 2ϩ channels have been implicated in a variety of cardiovascular diseases, including atrial fibrillation, 1,2 heart failure, 3-6 and ischemic heart disease. 7 Cardiac L-type Ca 2ϩ channels are regulated by a variety of neurotransmitters, hormones, and cytokines. In fact, the first description of currents carried by this channel revealed its regulation by epinephrine. 8 Sperelakis and Schneider 9 and Reuter and Scholz 10 independently hypothesized that ␤-adrenergic receptor (AR)-mediated stimulation of cardiac L-type Ca 2ϩ channels was due to phosphorylation of the channel by cAMP-dependent protein kinase A (PKA). Extensive electrophysiology experi...

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In-vivo phosphorylation of the cardiac L-type calcium channel beta-subunit in response to catecholamines

Cited by 60 publications

References 36 publications

Regulation of Cardiac L-Type Ca ²⁺ Channel Ca _V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

Regulation of Cardiac L-Type Ca ²⁺ Channel Ca _V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II

Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C

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In-vivo phosphorylation of the cardiac L-type calcium channel beta-subunit in response to catecholamines

Cited by 60 publications

References 36 publications

Regulation of Cardiac L-Type Ca 2+ Channel Ca V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

Regulation of Cardiac L-Type Ca 2+ Channel Ca V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II

Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C

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Regulation of Cardiac L-Type Ca ²⁺ Channel Ca _V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

Regulation of Cardiac L-Type Ca ²⁺ Channel Ca _V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway