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Muscarinic Agonists Evoke Neurotransmitter Release: Possible Roles for Phosphatidyl Inositol Bisphosphate Breakdown Products in Neuromodulation
Author(s) -
Diamant Sophia,
LevAri Itzhak,
Uzielli Illana,
Atlass Daphne
Publication year - 1988
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1988.tb01814.x
Subject(s) - muscarinic acetylcholine receptor , chemistry , carbachol , neurotransmitter , agonist , inositol phosphate , muscarinic agonist , endocrinology , inositol , muscarine , phospholipase c , second messenger system , medicine , pharmacology , receptor , biology , biochemistry
Carbachol (CCh), a muscarinic agonist that elicits the formation of inositol trisphosphate (IP3) and diacylglyc‐erol (DG), induces a calcium‐dependent [ 3 H]norepi‐nephrine ([ 3 H]NE) release [IC 50 = (2.7 ± 0.5) × 10 ‐4 M ] in rat brain slices. Similarly, other muscarinic agonists evoke [ 3 H]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 (IC 50 = 50 μ M ), 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 μ M (750 ng/ml). These results have a significant implication for the mechanism by which agonists generating IP 3 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 IP 3 /DG as second messengers followed by activation of PK‐C.