title: A direct effect of forskolin on sodium channel bursting.
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 (tau = 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 microM). 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-chlorophenylthio)-cAMP], or the phosphatase inhibitor okadaic acid. In addition, bursting was not augmented by guanosine 5'-O-(3-thiotriphosphate) (GTP [gamma S]) either applied to the bath or directly to the intracellular face of the channel in inside-out macropatches. Furthermore, 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, University of Chicago, IL 60637, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ono
authors.forename: H A
authors.initials: HA
authors.lastname: Fozzard
authors.forename: D A
authors.initials: DA
authors.lastname: Hanck
mesh_terms: D000818:Animals; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000187:drug effects*; D013997:Time Factors
chemical_list: D015222:Sodium Channels; D005576:Colforsin; D000242:Cyclic AMP