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

Weiss, Sharon W.; Oz, Shimrit; Benmocha, Adva; Dascal, Nathan

doi:10.1161/circresaha.113.301781

Cited by 101 publications

(67 citation statements)

References 198 publications

(277 reference statements)

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“…This substantial reduction of basal Ca V 1.2 channel activity in STAA ventricular myocytes agrees with previous studies of these same Ca V 1.2 mutations expressed in nonmuscle cells (10). Many signaling pathways are thought to contribute to control of the basal activity of Ca V 1.2 channels in cardiac myocytes (30). Classic studies of PKA regulation of L-type Ca 2+ current in guinea pig ventricular myocytes showed that inhibition of PKA with excess regulatory subunit or the peptide PKI reduced basal Ca 2+ currents significantly.…”

Section: Phosphorylation Of Ser1700 and Thr1704 Is Required For Normasupporting

confidence: 91%

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Westenbroek

Scheuer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The undersigned authors wish to note, "The KefFC system of E. coli is maintained in an inactive state by the binding of glutathione (GSH) and is activated by the formation of GSH adducts (GSX), particularly those with bulky substituents. We described two crystal structures with density present in the ligand-binding domain that we interpreted as GSH and GSX. Recently, an independent, experienced crystallographer, who had viewed the structures from our study in a different context, made representations to us that cast doubt on position of the succinimido ring of GSX. We have further reviewed the density maps with the aid of an experienced crystallographer. As a consequence, we believe it is important to draw this altered interpretation of the crystal structures to the attention of readers. In both structures, the density for the backbone of GSH is clear and allows unequivocal assignment of the position of the tripeptide. In PDB coordinate set 3L9X, the density for the succinimido ring is very weak, making interpretation very speculative and the assignment rests on the identity of the ligand added to the crystallization mixture, for which there are two diastereomers in the solutiona possibility that provides some basis for weakening the density. However, in 3L9W there are two anomalies that affect the interpretation of the bound ligand. First, there is no density for the carbon atom attached to the sulfur of GSH and second, there is extra density adjacent to the position of sulfur that could be modelled as a constrained succinimido ring. However, this density could also be water or any other molecule that is trapped in the structure. Thus, while there is good evidence for the peptide, the evidence that it is in the GSH form is uncertain."There are no new data on either the structures or on the gating mechanism. However, we believe that we should be cautious in interpreting the structural data and that the field in general should be made aware of the alternative views of the electron density data. Note that the mutagenesis and spectroscopic data that were presented in the original manuscript are not affected by this alternative interpretation." Tarmo P. The authors note that the following grant should be added to the Acknowledgments: "NIH Grant AG002132." The authors note "The method used for exogenous expression of Ca V 1.2 channels in ref. 32 was incorrectly described as 'viral transduction' in the text. In fact, Yang et al. created transgenic mice with inducible, cardiomyocyte-specific expression of exogenous Ca V 1.2 channels regulated by a tetracycline-inducible promoter. When crossed with a transgenic mouse line expressing doxycycline-regulated reverse transcriptional activator under control of the α-myosin heavy chain protomer, the resulting double transgenic offspring expressed exogenous Ca V 1.2 channels in their cardiac myocytes after treatment with doxycycline. The authors regret the error in describing these methods."www.pnas.org/cgi

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Section: Phosphorylation Of Ser1700 and Thr1704 Is Required For Normasupporting

confidence: 91%

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Westenbroek

Scheuer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The experiments presented here show that phosphorylation of this site is required for cardiac homeostasis and the prevention of heart failure in vivo. The mechanism of β-adrenergic/PKA stimulation of Ca V 1.2 channel activity in the fight-or-flight response has been controversial (7)(8)(9). However, the results of our previous experiments and those presented here leave no doubt about the importance of phosphorylation of Ser1700 in cardiovascular homeostasis and function.…”

Section: Discussionmentioning

confidence: 99%

“…In skeletal muscle, an additional γ subunit is associated with the closely related Ca V 1.1 channels (11,12). Multiple PKA sites have been identified by phosphorylation of purified preparations of α 1 1.2 (Ser1928) and β (Ser459, Ser478, and Ser479) subunits; however, none of these sites is required for β-adrenergic regulation of Ca V 1.2 channels in cardiac myocytes in vivo or in transfected mammalian cells (7,8). In addition to channel phosphorylation, the formation of an autoinhibitory signaling complex is also essential for β-adrenergic regulation of Ca V 1.2 channel activity (7,13,14).…”

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confidence: 99%

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Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Yang

Dai

Yuan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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L-type Ca 2+ currents conducted by voltage-gated calcium channel 1.2 (Ca V 1.2) initiate excitation-contraction coupling in the heart, and altered expression of Ca V 1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of Ca V 1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the Ca V 1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca 2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of Ca V 1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.calcium channel | heart failure | excitation-contraction coupling | PKA | casein kinase II E xcitation-contraction (EC) coupling in the heart is initiated by L-type calcium (Ca 2+ ) currents conducted by voltagegated calcium 1.2 (Ca V 1.2) channels that are activated by membrane depolarization (1). Ca 2+ influx via Ca V 1.2 channels activates Ca 2+ release from the sarcoplasmic reticulum (SR), leading to rapid and forceful contraction of myofilaments. Ryanodine receptor type-2 (RyR2) is the major channel for this release of Ca 2+ from cardiac SR (2, 3). Mobilized Ca 2+ is transported back into the SR by the SR Ca 2+ ATPase (SERCA) during muscle relaxation (4). SERCA activity is controlled by the inhibitor protein phospholamban (PLB), which is phosphorylated by PKA to release its inhibition of SERCA activity (4). The force and rate of cardiac contractions are critically dependent on the amplitude and kinetics of the Ca 2+ signal generated by Ca V 1.2 channels and RyR2 (1). In the fight-or-flight response, a marked increase in the beating rate and force of contraction of the heart is triggered by activation of the sympathetic nervous system and stimulation of the β-adrenergic signaling p...

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“…In human patients with Timothy syndrome, a G406R point mutation in Cav1.2 increases the channel activity and can lead to excessive insulin secretion and life-threatening hypoglycemia (Splawski et al 2004). PKA-dependent phosphorylation of Cav1.2 increases channel activity although the exact PKA site responsible for the regulation remains elusive (Weiss et al 2013). The potentiation of insulin secretion by cAMP is at least partially through PKA-mediated phosphorylation of Cav channels and increased Ca 2+ influx (Ammala et al 1993).…”

Section: Camp/pka In Pancreatic Isletsmentioning

confidence: 99%

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

151

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In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMPdependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

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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

Cited by 101 publications

References 198 publications

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

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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

Cited by 101 publications

References 198 publications

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response

Loss of β-adrenergic–stimulated phosphorylation of Ca V 1.2 channels on Ser1700 leads to heart failure

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

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Product

Resources

About

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

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure