INVOLVEMENT OF ENDOGENOUS NITRIC-OXIDE SIGNALING SYSTEM IN BRAIN MUSCARINIC ACETYLCHOLINE-RECEPTOR ACTIVATION

Biochemical signalling events coupled to muscarinic cholinergic recept ors (mAChR), specifically those related to nitric oxide (NO) productio n, were studied on rat cerebral frontal cortex. The mAChR agonist carb achol was found to exert a specific biphasic action on NO synthase (NO S) activity: low doses ranging between 10(-9)M to 10(-7)M lead to NOS activation while higher doses (>10(-6) M) inhibited enzymatic activity . Carbachol stimulatory action was blunted by agents that interfere wi th calcium-calmodulin while a protein kinase (PKC) inhibitor, staurosp orine was able to abrogate the inhibitory effect, Moreover, PKC activi ty showed maximum translocation to cerebral frontal cortex membranes w ith carbachol concentrations that inhibited NO production. Products fr om phosphoinosite (PI) hydrolysis are involved in these actions as car bachol was found to increase PI turnover in a dose dependent manner. T hese results would serve as an example of crosstalk between both enzym atic pathways.