Muscarinic Agonists Evoke Neurotransmitter Release: Possible Roles for Phosphatidyl Inositol Bisphosphate Breakdown Products in Neuromodulation

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Abstract
Carbachol (CCh), a muscarinic agonist that elicits the formation of inositol trisphosphate (IP3) and diacylglyc-erol (DG), induces a calcium-dependent [3H]norepi-nephrine ([3H]NE) release [IC50= (2.7 ± 0.5) × 10-4M] in rat brain slices. Similarly, other muscarinic agonists evoke [3H]NE release which is specifically inhibited by muscarinic antagonists such as 3-quinuclidinyl benzilate, atropine, and N-methyl-4-piperidyl benzilate. The atropine-sensitive evoked release is effectively inhibited by neomycin (IC50= 50 μM), a phospholipase C inhibitor that interferes with IP3-dependent cellular processes. In addition, polymyxin B, a rather selective inhibitor of protein kinase C (PK-C), abolishes the agonist-mediated release with a half-maximal effective concentration of 0.53 μM(750 ng/ml). These results have a significant implication for the mechanism by which agonists generating IP3 and DG act as inducers of neurotransmitter release in the CNS. However, since both neomycin and polymyxin B act also as N-calcium-channel blockers, other possible mechanisms are discussed. The CCh-induced release suggests that in the CNS an agonist-receptor interaction leads to a calcium-dependent neurotransmitter release, most likely via promoting the IP3/DG as second messengers followed by activation of PK-C.