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Mechanisms of Neuromodulation as Dissected Using Sr²⁺ at Motor Nerve Endings

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois

The use of binomial analysis as a tool for determining the sites of action of neuromodulators may be complicated by the nonuniformity of release probability. One of the potential sources for nonuniformity of release probability is the presence of multiple forms of synaptotagmins, the Ca²⁺ sensors responsible for triggering vesicular exocytosis. In this study we have used Sr²⁺, an ion whose actions may be restricted to a subpopulation of synaptotagmins, in an attempt to obtain meaningful estimates of the binomial parameters p (the probability of evoked acetylcholine [Ach] release) and n (the immediate available store of ACh quanta, whereby m = np). In contrast to results in Ca²⁺ solutions, binomial analysis of Sr²⁺-dependent release reveals a dramatically reduced dependence of n on extracellular Sr²⁺ concentrations. In Sr²⁺ solutions, blockade of potassium channels with 3,4-diaminopyridine increased m by an exclusive increase in p, whereas treatment with phorbol ester increased m solely by effects on n. The cyclic adenosine monophosphate (cAMP) analogue CPT-cAMP increased m by increasing both n and p. The effect of CPT-cAMP on p but not on n was blocked by protein kinase A (PKA) inhibitors, whereas the effect on n was mimicked by 8-CPT-2'-O-Me-cAMP, a selective agonist for exchange protein directly activated by cAMP, otherwise known as the cAMP-sensitive guanine nucleotide-exchange protein. The results demonstrate both the utility of the binomial distribution in Sr²⁺ solutions and the dual effects of cyclic AMP on both PKA-dependent and PKA-independent processes at the amphibian neuromuscular junction.