Muscarinic agonists evoke neurotransmitter release: possible roles for phosphatidyl inositol bisphosphate breakdown products in neuromodulation.
Carbachol (CCh), a muscarinic agonist that elicits the formation of inositol trisphosphate (IP3) and diacylglycerol (DG), induces a calcium-dependent [3H]norepinephrine ([3H]NE) release [IC50 = (2.7 +/- 0.5) X 10(-4) M] 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 microM), 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 microM (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.
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D066298:In Vitro Techniques; D009116:Muscarine / Q000037:antagonists & inhibitors / Q000502:physiology*; D009355:Neomycin / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010277:Parasympathomimetics / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011112:Polymyxin B / Q000494:pharmacology; D014403:Tubocurarine / Q000494:pharmacology
D018377:Neurotransmitter Agents; D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D009538:Nicotine; D009116:Muscarine; D009355:Neomycin; D011112:Polymyxin B; D002118:Calcium; D014403:Tubocurarine; D009638:Norepinephrine