ISSN:
1432-2013
Keywords:
Voltage clamp
;
Cardiac Na channels
;
Macropatch recording
;
H-89
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract A long-lasting component of current through voltage-dependent Na channels is believed to contribute to the plateau phase of the cardiac action potential. Here we report that in cardiac ventricular myocytes forskolin increases the contribution of a very slow component of decay (τ=36±16 ms,n=13) in ensemble currents in response to step depolarizations to 0 mV. Long-lasting bursts of openings (mean duration of 27±14 ms,n=10) accounted for this behavior. The slow time constant of decay was not altered by forskolin (5–50 μM). Rather, an increase in the probability of bursting behavior produced a forskolin concentration-dependent increase in the amplitude of this very slow component. This action of forskolin was not the result of stimulation of adenylyl cyclase because it was not affected when cAMP-dependent phosphorylation was inhibited by the protein kinase inhibitor H-89, and it could not be mimicked by addition of isoproterenol, membrane-permeant cAMP [8-(4-chloro-phenylthio)-cAMP], or the phosphatase inhibitor okadaic acid. In addition, bursting was not augmented by guanosine 5′-O-(3-thiotriphosphate) (GTP [γS]) either applied to the bath or directly to the intracellular face of the channel in inside-out macropatches. Further-more, 1,9-dideoxy-forskolin, which does not stimulate adenylyl cyclase and 6-(3-dimethylaminopropionyl)-forskolin, a hydrophilic derivative of forskolin, also augmented late channel activity. Comparison of the characteristics of bursts in the presence of forskolin with those occurring in its absence suggested that the increase in the frequency of long-lasting bursts produced by forskolin represents a direct interaction of forskolin with the channel that augments, by up to tenfold, the probability that channels will have delayed inactivation.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00704162
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