Can PKA activators rescue Na+ channel function in epicardial border zone cells that survive in the infarcted canine heart?
OBJECTIVE
In this study, we investigated the effects of a PKA stimulating cocktail on sodium currents from normal epicardial cells (NZs) and on those from cells dispersed from the epicardial zone of the 5-day infarcted canine heart (IZs). To do so, we used whole-cell voltage-clamp techniques.


RESULTS
During superfusion with the PKA activator cocktail, peak sodium current (I(Na)) density significantly increased by 32+/-5.3% (NZs) and 17+/-5.4% (IZs). However, despite this increase, IZ peak I(Na) still was not fully restored to NZ values. In both cell types, the density effect was accompanied by a shift in I/I(max) curves, as well as a slowing in recovery from inactivation. Inactivation from a closed state was accelerated. Furthermore, in the presence of chloroquine, which is known to interrupt intracellular vesicular traffic, PKA activator effects to augment I(Na) were only partially inhibited in NZs but abolished in IZs. To understand whether the phosphorylation status of basal Na(+) channels in the two cell groups differed, the effects of okadaic acid and PP2A1 were studied. Results suggest that in IZs, Na(+) channels in the basal state are already phosphorylated.


CONCLUSIONS
PKA stimulation of I(Na) of the remodeled IZ does augment current density possibly by augmenting the trafficking of channels to an active site on the membrane. However, the resulting I(Na), while partially rescued, is not similar to the potentiated I(Na) of NZs. Specific kinetic changes also occur with the PKA stimulation of IZs and results with okadaic acid and PP2A1 suggest that in their remodeled state, Na(+) channels in IZs are already phosphorylated.
Baba
Shigeo
S
Department of Pharmacology, Columbia University, New York, NY, USA.
Dun
Wen
W
Boyden
Penelope A
PA
D000704:Analysis of Variance; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000187:drug effects*; D020257:Ventricular Remodeling
D002120:Calcium Channel Agonists; D015222:Sodium Channels; D019319:Okadaic Acid; D017868:Cyclic AMP-Dependent Protein Kinases