title: Adrenergic signaling controls RGK-dependent trafficking of cardiac voltage-gated L-type Ca2+ channels through PKD1.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Bong Sook
authors.initials: BS
authors.lastname: Jhun
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Jin
authors.initials: J
authors.lastname: O-Uchi
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Weiye
authors.initials: W
authors.lastname: Wang
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Ha
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Jinjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Wong
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Coeli M B
authors.initials: CMB
authors.lastname: Lopes
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester NY, 14642 USA.
authors.forename: Zheng Gen
authors.initials: ZG
authors.lastname: Jin
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D008297:Male; D008870:Microtubules / Q000502:physiology; D023421:Models, Animal; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011493:Protein Kinase C; D011494:Protein Kinases / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020746:Calcium Channels, L-Type; D018340:Receptors, Adrenergic, alpha-1; C570832:Rem1 protein, rat; D011494:Protein Kinases; C089212:protein kinase D; D011493:Protein Kinase C; D020559:Monomeric GTP-Binding Proteins
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