1. Adrenergic signaling controls RGK-dependent trafficking of cardiac voltage-gated L-type Ca2+ channels through PKD1.
- Author
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Jhun BS, O-Uchi J, Wang W, Ha CH, Zhao J, Kim JY, Wong C, Dirksen RT, Lopes CMB, and Jin ZG
- Subjects
- Animals, Cell Membrane physiology, Cells, Cultured, Male, Microtubules physiology, Models, Animal, Monomeric GTP-Binding Proteins physiology, Myocytes, Cardiac cytology, Patch-Clamp Techniques, Phosphorylation, Protein Kinase C, Rats, Rats, Sprague-Dawley, Calcium Channels, L-Type physiology, Myocytes, Cardiac physiology, Protein Kinases physiology, Protein Transport physiology, Receptors, Adrenergic, alpha-1 physiology, Signal Transduction physiology
- 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
- 2012
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