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

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.