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 (I-A) in cultured rat hippocampal neurons. This ef fect has been further demonstrated to be dependent on G-protein linkag e to adenylyl cyclase and levels of intracellular cyclic AMP (cAMP). T he present study extends this analysis to the involvement of cAMP-depe ndent protein kinase (PKA) in this cascade. Specific activators and in hibitors of PKA were shown to have differential effects on the voltage dependence of I-A. Specific activators of PKA produced a negative shi ft in voltage dependence of I-A, whereas PKA inhibitors produced a pos itive shift in I-A voltage dependence, the latter similar to that effe cted by the cannabinoid agonist WIN 55,212-2. Although the negative sh ift in I-A induced by PKA stimulation could be reversed by PKA inhibit ors, the positive shift produced by the PKA inhibitors alone was only 50-60% of the cannabinoid-produced shift in I-A voltage dependence. Th is partial effect of PKA. inhibition was confirmed by biochemical assa ys in the same cultured neurons that showed a similar 50-60% decrement in in vitro protein phosphorylation produced by PKA inhibitors. Resul ts are discussed in terms of a diffusible second messenger linkage of the cannabinoid receptor to the A-current channel via the role of prot ein phosphorylation in modulation of I-A.