1. Adrenergic signaling controls RGK-dependent trafficking of cardiac voltage-gated L-type Ca2+ channels through PKD1
- Author
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Coeli M. Lopes, Ji Young Kim, Bong Sook Jhun, Robert T. Dirksen, Chelsea Wong, Weiye Wang, Chang Hoon Ha, Jinjing Zhao, Jin O-Uchi, and Zheng Gen Jin
- Subjects
Male ,Patch-Clamp Techniques ,Adrenergic receptor ,Calcium Channels, L-Type ,Physiology ,Adrenergic ,Biology ,Microtubules ,Article ,Rats, Sprague-Dawley ,Receptors, Adrenergic, alpha-1 ,Animals ,Myocytes, Cardiac ,Phosphorylation ,Protein kinase C ,Cells, Cultured ,Protein Kinase C ,Monomeric GTP-Binding Proteins ,Voltage-dependent calcium channel ,Voltage-gated ion channel ,Calcium channel ,Cell Membrane ,Cell biology ,Rats ,Protein Transport ,Models, Animal ,Protein kinase D1 ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Protein Kinases ,Signal Transduction - Abstract
Rationale: The Rad-Gem/Kir-related family (RGKs) consists of small GTP-binding proteins that strongly inhibit the activity of voltage-gated calcium channels. Among RGKs, Rem1 is strongly and specifically expressed in cardiac tissue. However, the physiological role and regulation of RGKs, and Rem1 in particular, are largely unknown. Objective: To determine if Rem1 function is physiologically regulated by adrenergic signaling and thus impacts voltage-gated L-type calcium channel (VLCC) activity in the heart. Methods and Results: We found that activation of protein kinase D1, a protein kinase downstream of α 1 -adrenergic signaling, leads to direct phosphorylation of Rem1 at Ser18. This results in an increase of the channel activity and plasma membrane expression observed by using a combination of electrophysiology, live cell confocal microscopy, and immunohistochemistry in heterologous expression system and neonatal cardiomyocytes. In addition, we show that stimulation of α 1 -adrenergic receptor-protein kinase D1-Rem1 signaling increases transverse-tubule VLCC expression that results in increased L-type Ca 2+ current density in adult ventricular myocytes. Conclusion: The α 1 -adrenergic stimulation releases Rem1 inhibition of VLCCs through direct phosphorylation of Rem1 at Ser18 by protein kinase D1, resulting in an increase of the channel activity and transverse-tubule expression. Our results uncover a novel molecular regulatory mechanism of VLCC trafficking and function in the heart and provide the first demonstration of physiological regulation of RGK function.
- Published
- 2011