| Co-Investigator(Kenkyū-buntansha) |
HASHIMOTO Hitoshi Osaka University, Faculty of Pharmaceutical Sciences, Assistant Researcher, 薬学部, 助手 (30240849)
MATSUDA Toshio Osaka University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (00107103)
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| Research Abstract |
PACAP has an amino acid sequence identity of 68% with vasoactive intestinal polypeptide (VIP) and regulates a wide range of physiological functions in the central and peripheral nervous systems. Three genes encoding PACAP/VIP receptor subtypes, which bind PACAP with a high affinity, have been cloned, but the physiological significance of each subtype has not been completely characterized. To elucidate the role of the PACAP signaling system, we have used gene targeting in embryonic stem cells to disrupt exon 2 of the PACAP receptor gene, and characterized the mutant mice as well as wildtype mice.
1. The mutant mice had reduced [^<125>I]PACAP-27 binding and cAMP production in their brains.
2. The mutant mice, however, were viable and fertile, and morphologically, histologically and electrophysiologically indistinguishable from their wild-type counterparts.
3. Coexpression of PACAP receptor and PACAP was seen in the sympathetic nervous system of the wild-type mice and rats.
4. In the sympathetic neurons, PACAP stimulates the expression of PACAP receptor and PACAP mRNAs at a transcriptional level.
5. The mechanism of the PACAP production was studied in mouse insulinoma cells.
In conclusion, these results suggest that PACAP acts as a autocrine or paracrine regulatory factor and contributes to sustained activation of the sympathoadrenal system, and that PACAP regulates glucose-stimulated insulin secretion from beta cells by an autocrine mechanism. However, the intact PACAP receptor is not a prerequisite for normal mouse development of for survival.
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