PC12 cells, rat pheochromocytoma cells, are neuroendocrine cells and widely used for the study of exocytosis. PC12 cells release catecholamine (CA) from vesicles in response to the neurotransmitter acetylcholine (ACh) by the fusion of the vesicle membrane and the cell membrane. In the models of neurodegenerative disorders, such as Alzheimer's disease (AD), alteration of exocytosis mechanisms has been reported. Humanin (HN) is a 24-residue polypeptide and initially identified as a neuroprotective factor against AD-related insults. HN suppresses neuronal death caused by amyloid beta, an AD-associated cytotoxic insult, in vitro and ameliorates memory deficit of AD mouse models. We have recently found that HN increases the levels of neurotransmitters including catecholamines in the hippocampal region of normal mice. This finding suggests that HN may have the direct effect on promoting exocytosis in neurons. In this study, we examined the effect of S14G-HN (HNG), a highly potent HN derivative, on exocytosis. In PC12 cells, HNG increased ACh-induced CA secretion by the Bath application experiment. On the other hand, neuroprotection-defective HN derivatives, S7A-HN and C8A-HN, did not affect CA secretion. Furthermore, no secretagogue activity of HNG was observed by inhibiting JAK, a signal molecule of gp130 receptor. These results suggest that the receptor-mediated JAK-STAT pathway is involved in the HN's activity for promoting exocytosis.
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