Beta-adrenergic regulation of the heart expressing the Ser1700A/Thr1704A mutated Cav1.2 channel

Poomvanicha, Montatip; Matthes, Jan; Domes, Katrin; Patrucco, Enrico; Angermeier, Elisabeth; Laugwitz, Karl‐Ludwig; Schneider, Toni; Hofmann, Franz

doi:10.1016/j.yjmcc.2017.07.119

Cited by 12 publications

(14 citation statements)

References 40 publications

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“…The studies with knock-in mice also revealed limitations in this model system with respect to elucidating mechanisms of PKA modulation of Ca V 1.2. The ST/AA knock-in mice develop cardiac hypertrophy while Ca V 1.2PKA_P2 −/− mice display evidence of compensatory mechanisms to overcome the decreased basal I Ca,L [31, 33]. This is consistent with previous observations that decreasing Ca V 1.2 by gene dosage in α 1C +/− heterozygous mice leads to cardiac hypertrophy and heart failure [34].…”

Section: Regulation Of Cav12 Channels By Pka Phosphorylationsupporting

confidence: 87%

“…Somewhat discrepant results and interpretation were obtained for a similar Ca V 1.2[S1700A, Thr1704A] knock-in mouse, termed Ca V 1.2PKA_P2 −/− , generated by the Hofmann group [33]. Similar to the ST/AA mice, cardiomyocytes from Ca V 1.2PKA_P2 −/− displayed a reduced basal I Ca,L amplitude compared to wild-type controls.…”

Section: Regulation Of Cav12 Channels By Pka Phosphorylationmentioning

confidence: 99%

“…The critical difference between the two reports is that the Ca V 1.2PKA_P2 −/− displayed a substantive decrease in α 1C expression (assessed by Western blotting) that could account for the decrease in basal current. The fold increase in current with isoproterenol was similar between control and Ca V 1.2PKA_P2 −/− mice, indicating normal PKA regulation of the remnant channels[33]. Hence, data from the Ca V 1.2PKA_P2 −/− mice do not support an important role for Ser1700/Thr1704 in the acute PKA modulation of I Ca,L .…”

Section: Regulation Of Cav12 Channels By Pka Phosphorylationmentioning

confidence: 99%

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Regulation of microdomain voltage-gated L-type calcium channels in cardiac health and disease

Shuja

Colecraft

2018

Current Opinion in Physiology

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Cav1.2 channels in the heart mediate excitation-contraction (E-C) coupling; tune cardiac excitability; and regulate gene expression. In ventricular myocytes, Ca1.2 channels are predominantly located in t-tubules where they are in proximity to ryanodine receptors to trigger cardiac E-C coupling. A subset of ventricular Ca1.2 channels existing on the surface sarcolemma, including in caveolae, have less well-defined functions. Cardiac Ca1.2 channels are famously up-regulated by protein kinase A as a component of the 'fight-or-flight' response. The molecular details of how this kinase regulates cardiac Ca1.2 channels are controversial and under intensive study. Here, we critically review recent work addressing the putative functions of microdomain cardiac Ca1.2 channels, and their regulation by distinct kinases in health and disease.

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Section: Regulation Of Cav12 Channels By Pka Phosphorylationsupporting

confidence: 87%

Section: Regulation Of Cav12 Channels By Pka Phosphorylationmentioning

confidence: 99%

Section: Regulation Of Cav12 Channels By Pka Phosphorylationmentioning

confidence: 99%

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Regulation of microdomain voltage-gated L-type calcium channels in cardiac health and disease

Shuja

Colecraft

2018

Current Opinion in Physiology

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“…Their metric is valid only if the density of Ca 2+ channels at the surface was unchanged, yet basal Ca 2+ currents were substantially reduced [56,57]. Hofmann and colleagues subsequently created S1700A/T1704A knock-in mice and concluded that isoproterenol stimulated Ca 2+ current in the control and mutant S1700A/T1704A cardiomyocytes to the same extent [58]. Furthermore, Hofmann's group recalculated Catterall's data and showed that in both groups' knock-in mice, the β-adrenergic stimulation for wild-type and mutant channels were equivalent [58].…”

Section: Additional Phosphorylation Sitesmentioning

confidence: 99%

“…Hofmann and colleagues subsequently created S1700A/T1704A knock-in mice and concluded that isoproterenol stimulated Ca 2+ current in the control and mutant S1700A/T1704A cardiomyocytes to the same extent [58]. Furthermore, Hofmann's group recalculated Catterall's data and showed that in both groups' knock-in mice, the β-adrenergic stimulation for wild-type and mutant channels were equivalent [58]. This confirmed our initial findings [54], which we have further substantiated with additional transgenic mice [59,60].…”

Section: Additional Phosphorylation Sitesmentioning

confidence: 99%

The quest to identify the mechanism underlying adrenergic regulation of cardiac Ca²⁺ channels

2020

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Activation of protein kinase A by cyclic AMP results in a multi-fold upregulation of Ca V 1.2 currents in the heart, as originally reported in the 1970's and 1980's. Despite considerable interest and much investment, the molecular mechanisms responsible for this signature modulation remained stubbornly elusive for over 40 years. A key manifestation of this lack of understanding is that while this regulation is readily apparent in heart cells, it has not been possible to reconstitute it in heterologous expression systems. In this review, we describe the efforts of many investigators over the past decades to identify the mechanisms responsible for the β-adrenergic mediated activation of voltage-gated Ca 2+ channels in the heart and other tissues.

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Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

Chen

Wang

et al. 2021

Clinical & Translational Med

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Cardiac voltage‐gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC‐related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life‐threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart‐related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well‐studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.

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Beta-adrenergic regulation of the heart expressing the Ser1700A/Thr1704A mutated Cav1.2 channel

Cited by 12 publications

References 40 publications

Regulation of microdomain voltage-gated L-type calcium channels in cardiac health and disease

Regulation of microdomain voltage-gated L-type calcium channels in cardiac health and disease

The quest to identify the mechanism underlying adrenergic regulation of cardiac Ca²⁺ channels

Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

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Beta-adrenergic regulation of the heart expressing the Ser1700A/Thr1704A mutated Cav1.2 channel

Cited by 12 publications

References 40 publications

Regulation of microdomain voltage-gated L-type calcium channels in cardiac health and disease

Regulation of microdomain voltage-gated L-type calcium channels in cardiac health and disease

The quest to identify the mechanism underlying adrenergic regulation of cardiac Ca2+ channels

Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

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Product

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The quest to identify the mechanism underlying adrenergic regulation of cardiac Ca²⁺ channels