Localization and modulation of {alpha}1D (Cav1.3) L-type Ca channel by protein kinase A

Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2123-30. doi: 10.1152/ajpheart.01023.2004. Epub 2004 Dec 22.

Abstract

Alpha1D L-type Ca channel was assumed to be of neuroendocrine origin only; however, alpha1D L-type Ca channel knockout mice exhibit sinus bradycardia and atrioventricular block, indicating a distinct role of alpha1D in the heart. The presence and distribution of alpha1D Ca channel in the heart and its regulation by protein kinase A (PKA) are just emerging. Our objective was to examine the localization of alpha1D L-type Ca channel in rabbit and rat hearts and its modulation by PKA. Here, we show the exclusive presence of alpha1D Ca channel transcript in the sinoatrial node, atrioventricular node, and atria but not in the ventricle by RT-PCR and the expression of alpha1D Ca channel protein in atrial myocytes' sarcolemma by indirect immunostaining and Western blot. There is no significant difference in the expression level of alpha1D Ca channel in the left versus right atrium. Superfusion of membrane-permeable 8-bromo-cAMP resulted in a significant increase of the peak current density of alpha1D Ca current expressed in tsA201 cells. This increase was inhibited by the PKA inhibitor (PKI). Application of 8-bromo-cAMP also readily phosphorylated the alpha1D Ca channel protein. The results are first to demonstrate that PKA phosphorylation of L-type Ca channel alpha1D-subunit resulted in an increase of the alpha1D Ca channel activity. Together with the observation that alpha1D Ca channel is exclusively present in the sinoatrial node and atria, the findings suggest that alpha1D Ca channel plays a unique role in the sinoatrial tissue and is a target for sympathetic control of heart rhythm.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Animals
  • Calcium Channels, L-Type / genetics*
  • Calcium Channels, L-Type / metabolism*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Heart Atria / metabolism
  • Heart Ventricles / metabolism
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Phosphorylation
  • RNA, Messenger / analysis
  • Rabbits
  • Sinoatrial Node / physiology*
  • Sympathetic Nervous System / physiology

Substances

  • Cacna1d protein, mouse
  • Calcium Channels, L-Type
  • RNA, Messenger
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases