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  • Title: Mechanism of alpha-latrotoxin action at nerve endings of neurohypophysis.
    Author: Hlubek M, Tian D, Stuenkel EL.
    Journal: Brain Res; 2003 Nov 28; 992(1):30-42. PubMed ID: 14604770.
    Abstract:
    The neurotoxin alpha-latrotoxin elicits spontaneous exocytosis of neurotransmitter from neurons and peptide hormones from endocrine cells. While the mechanism of action is not fully understood, both Ca(2+)-dependent and Ca(2+)-independent pathways participate in the facilitation of release, with the relative contribution of the pathways differing among neuronal and endocrine cell types. Here, we investigate the actions of alpha-latrotoxin on neuroendocrine nerve endings that emanate from central nervous system neurons and, therefore, are unique in that they possess properties of central nerve endings and endocrine cells. Using intracellular [Ca(2+)] measurements both calcium-independent receptors for latrotoxin (CIRL or latrophilin) and neurexin 1 alpha receptors were found to be functionally present. Interaction of alpha-latrotoxin with these receptors stimulated secretion of vasopressin and oxytocin neuropeptide. The secretory response was entirely dependent upon toxin-mediated extracellular Ca(2+) influx, although alpha-latrotoxin also consistently triggered mobilization of Ca(2+) from an intracellular store. The mobilization of intracellular Ca(2+) relied on alpha-latrotoxin-mediated Na(+) influx and was blocked by the protonophore FCCP, thereby implicating mitochondria as the Ca(2+) store being mobilized. Using the whole cell recording configuration of the patch clamp, we report that alpha-latrotoxin interaction with the CIRL receptor on these nerve endings resulted in ionic pore formation, generating unitary inward current steps of 20 pA and a channel conductance of approximately 220 pS in Ca(2+)-free saline. Thus, alpha-latrotoxin stimulates Ca(2+)-dependent exocytosis in neurohypophysial nerve endings through receptor interaction and insertion of Ca(2+) permeable membrane pores. While alpha-latrotoxin mobilizes intracellular Ca(2+) stores the elevation in [Ca(2+)] reached is insufficient to trigger measurable exocytosis.
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