Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium "A-current" in cultured rat hippocampal neurons.
Cannabinoid receptor agonists have been previously shown to enhance a potassium A-current (IA) in cultured rat hippocampal neurons. This effect has been further demonstrated to be dependent on G-protein linkage to adenylyl cyclase and levels of intracellular cyclic AMP (cAMP). The present study extends this analysis to the involvement of cAMP-dependent protein kinase (PKA) in this cascade. Specific activators and inhibitors of PKA were shown to have differential effects on the voltage dependence of IA. Specific activators of PKA produced a negative shift in voltage dependence of IA, whereas PKA inhibitors produced a positive shift in IA voltage dependence, the latter similar to that effected by the cannabinoid agonist WIN 55,212-2. Although the negative shift in IA induced by PKA stimulation could be reversed by PKA inhibitors, the positive shift produced by the PKA inhibitors alone was only 50-60% of the cannabinoid-produced shift in IA voltage dependence. This partial effect of PKA inhibition was confirmed by biochemical assays in the same cultured neurons that showed a similar 50-60% decrement in in vitro protein phosphorylation produced by PKA inhibitors. Results are discussed in terms of a diffusible second messenger linkage of the cannabinoid receptor to the A-current channel via the role of protein phosphorylation in modulation of IA.
Hampson
R E
RE
Department of Physiology & Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.
Evans
G J
GJ
Mu
J
J
Zhuang
S Y
SY
King
V C
VC
Childers
S R
SR
Deadwyler
S A
SA
D000818:Animals; D002186:Cannabinoids / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D015640:Ion Channel Gating; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D010766:Phosphorylation; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000502:physiology*
D002186:Cannabinoids; D015221:Potassium Channels; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases