Intracellular Na+ modulates the cAMP-dependent regulation of ion channels in the heart.
The cAMP-dependent regulation of ion channels was studied by using the whole-cell configuration of the patch clamp technique. In isolated cardiac ventricular myocytes, the beta-adrenergically regulated Cl- current (ICl) exhibited an unusual dependence on Na+, such that replacement of extracellular Na+ with compounds such as tetramethylammonium, choline, Tris, or N-methyl-D-glucamine resulted in a reduction in current amplitude without changing the reversal potential. Replacement of extracellular Na+ with tetramethylammonium also reduced the magnitude of the beta-adrenergically enhanced Ca2+ current and delayed rectifier K+ current, suggesting that removal of Na+ was affecting the cAMP pathway that regulates all three currents. Replacement of extracellular Na+ also reduced ICl that was stimulated by (i) direct activation of adenylate cyclase with forskolin, (ii) inhibition of phosphodiesterase with 3-isobutyl-1-methylxanthine, (iii) exposure to the membrane-permeable cAMP derivative 8-bromoadenosine 3',5'-cyclic monophosphate, or (iv) direct phosphorylation of the channel with protein kinase A catalytic subunit. This suggests that the Na+ dependence is at a point beyond the activation of protein kinase A. The Na+ dependence of ICl regulation could not be explained by changes in intracellular Ca2+. However, the sensitivity of the ICl to changes in extracellular Na+ depended significantly on the intracellular Na+ concentration, suggesting that intracellular Na+ plays an important role in the cAMP-dependent regulation of ion channels.
Harvey
R D
RD
Department of Physiology, University of Nevada School of Medicine, Reno 89557.
Jurevicius
J A
JA
Hume
J R
JR
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018118:Chloride Channels; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D006706:Homeostasis; D007473:Ion Channels / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology*; D012964:Sodium / Q000502:physiology*
D015220:Calcium Channels; D018118:Chloride Channels; D007473:Ion Channels; D008565:Membrane Proteins; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D012964:Sodium; D000242:Cyclic AMP; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine