1,9-Dideoxyforskolin does not mimic all cAMP and protein kinase A independent effects of forskolin on GABA activated ion currents in adult rat sensory neurons.
The effect of forskolin on GABAA receptor activated events has been the subject of recent investigations, the conclusions of which are conflicting. Forskolin can reduce current amplitude and increase the rate of decay of current activated by 100 microM GABA and these effects are not mimicked by 1,9-dideoxyforskolin (Tehrani et al., Synapse, 4 (1989) 126-131). On the other hand, both forskolin and 1,9-dideoxyforskolin inhibit 36Cl- flux induced by lower concentrations of muscimol (Heuschneider and Schwartz, Proc. Natl. Acad. Sci. USA, 86 (1989) 2938-2942). Using the whole-cell patch clamp technique to measure GABA activated current in dorsal root ganglion neurons that were freshly isolated from adult rats, we have confirmed the finding of Tehrani et al. (Synapse, 4 (1989) 126-131) using 100 microM GABA; however, the effects of forskolin that were not mimicked by 1,9-dideoxyforskolin were not blocked by the kinase inhibitor H-7 (50 microM). In contrast, at lower concentrations of GABA (10-20 microM), both forskolin and 1,9-dideoxyforskolin increased the decay rate of GABA activated current. In addition, all effects of forskolin occurred within 200 ms of application of forskolin and the effects were not blocked or occluded by H-7, 10 microM cAMP, or the active subunit of protein kinase A. We conclude that: (1) 1,9-dideoxyforskolin is not a reliable indicator of forskolin specificity in this system because its effects are dependent upon GABA concentration; and (2) the most prominent effects of forskolin on amplitude and decay time course of GABA activated ion current are not mediated by cAMP or protein kinase A (PKA).
White
G
G
Section of Electrophysiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20852.
Li
C
C
Ishac
E
E
D000818:Animals; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D004553:Electric Conductivity; D007473:Ion Channels / Q000502:physiology*; D009475:Neurons, Afferent / Q000378:metabolism*; D011494:Protein Kinases / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D007473:Ion Channels; D005576:Colforsin; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D011494:Protein Kinases; C047983:1,9-dideoxyforskolin