Cardiac CaV1.2 channels require β subunits for β-adrenergic–mediated modulation but not trafficking

Abstract

Statistics. Results are mean ± SEM. For multiple group comparisons, 1-way ANOVA followed by multiple comparison testing was performed. For comparisons between 2 groups, an unpaired Student's t test was used. Statistical analyses were performed using Prism 6 (Graphpad Software). Differences were considered statistically significant at P values less than 0.05. Data availability. The data and study materials will be made available to other researchers for purposes of reproducing the results or replicating the procedure. Study approval. The Institutional Animal Care and Use Committee at Columbia University approved all animal experiments.

β‐adrenergic‐mediated dynamic augmentation of sarcolemmal CaV1.2 clustering and co‐operativity in ventricular myocytes

“…When the current manuscript was under consideration, an interesting study was published reporting that AID mutant Ca V 1.2 channels, unable to bind Ca V β subunits, are insensitive to βAR stimulation with ISO or the adenylyl cyclase activator forskolin. (Yang et al ., ). The results of the present study showing dynamic augmentation of Ca V 1.2 and Ca V β 2a sarcolemmal expression upon stimulation with ISO (Figs and ) have relevance to this work, and shed more light on the importance of the Ca V β subunit in adrenergic regulation of Ca V 1.2.…”

Roles and Regulation of Voltage-gated Calcium Channels in Arrhythmias

“…61 Instead, we found that β-subunit binding to the Ca V 1.2 α 1C subunit, but not PKA phosphorylation of β, is absolutely essential for the augmentation of Ca 2+ current and cardiac contractile response to β-adrenergic−related PKA stimulation. 13 These findings identify the key regulatory mechanisms impacting β-adrenergic regulation of Ca 2+ influx and contractility in the heart. Ca V 1.2 is also a major target of CaMKII, and the resulting Ca 2+ -dependent facilitation of Ca V 1.2 current, observed as a positive "staircase" of Ca 2+ current in which current amplitude increases and inactivation slows over a series of repetitive pulses, is a powerful feed-forward effect on Ca 2+ signaling in the heart.…”

“…With this new model, we definitively demonstrate in vivo that the β subunit binding to α 1C is not required for trafficking and that the basal function of β-less Ca +2 channels is only minimally altered. 13 The α 2 δ subunit is a 175-kDa single transmembrane protein encoded by four genes (Cacna2d1, Cacna2d2, Cacna2d3, and Cacna2d4) with multiple splice variants. Although the messenger RNAs of α 2 δ 1 through 3 14 have been identified in human myocardium, only α 2 δ-1 is known to bind with Ca V 1.2 (Figure 1).…”

Designer genetically encoded voltage‐dependent calcium channel inhibitors inspired by RGK GTPases

“…Further, a transgenic mouse expressing a dihydropyridine‐resistant α 1C mutant that does not bind Ca V β displayed ample DHP‐resistant Ca V 1.2 current, indicating a robust Ca V β‐independent trafficking to the sarcolemma (Yang et al . 2019). It remains to be determined whether and to what extent Ca V β‐independent trafficking happens in other cell types and other Ca V 1/Ca V 2 isoforms at different developmental stages.…”