Adrenergic signaling controls RGK-dependent trafficking of cardiac voltage-gated L-type Ca 2+ channels through PKD1

Bong Sook Jhun, Jin Ouchi, Weiye Wang, Chang Hoon Ha, Jinjing Zhao, Ji Young Kim, Chelsea Wong, Robert T. Dirksen, Coeli M.B. Lopes, Zheng Gen Jin

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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 α1-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 α1-adrenergic receptor-protein kinase D1-Rem1 signaling increases transverse-tubule VLCC expression that results in increased L-type Ca current density in adult ventricular myocytes. Conclusion: The α1-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.

Original languageEnglish (US)
Pages (from-to)59-70
Number of pages12
JournalCirculation research
Volume110
Issue number1
DOIs
StatePublished - Jan 6 2012

Keywords

  • adrenoceptor
  • patch clamp
  • phenylephrine

Fingerprint Dive into the research topics of 'Adrenergic signaling controls RGK-dependent trafficking of cardiac voltage-gated L-type Ca <sup>2+</sup> channels through PKD1'. Together they form a unique fingerprint.

Cite this