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Volume 16, Number 21, Issue of November 1, 1996 pp. 6695-6702
Copyright ©1996 Society for Neuroscience

A Murine Neural-Specific Homolog Corrects Cholinergic Defects in Caenorhabditis elegans unc-18 Mutants

Received March 11, 1996; revised Aug. 8, 1996; accepted Aug. 13, 1996.

Keiko Gengyo-Ando^{1, 2}, Hitoshi Kitayama^{1, 3}, Masahiro Mukaida², and Yoji Ikawa^{1, 4}

¹ Laboratory of Molecular Oncology, The Institute of Physical and Chemical Research (RIKEN), Tsukuba, Ibaraki 305, Japan, ² Department of Forensic Medicine, National Defense Medical College, Tokorozawa, Saitama 359, Japan, ³ Department of Molecular Oncology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606, Japan, and ⁴ Department of Retroviral Regulation, Medical Research Division, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113, Japan

Caenorhabditis elegans UNC-18 protein, homologous to yeast Sec1p, is important in neurotransmitter release, because the unc-18 mutation leads to severe paralysis and presynaptic acetylcholine (ACh) accumulation. To examine the functional conservation in mammals, we tried to isolate unc-18 isoforms from mouse and human brain cDNA libraries and obtained two classes of isoformsneural genes and ubiquitous genes. Neural genes were identical to Munc-18 (also known as n-Sec1 or rbSec1), identified in rat and bovine brains as a syntaxin-binding protein. According to ``Munc-18'' terminology, we call the neural genes Munc-18-1 and the ubiquitous genes Munc-18-3. These mammalian isoforms exhibit 58% (Munc-18-1) and 42-43% (Munc-18-3) amino acid sequence identity with UNC-18. Next, we constructed transgenic unc-18 mutants to test biological activity of mouse Munc-18-1 and Munc-18-3 under the control of C. elegans unc-18 promoter. Munc-18-1 compensates for severe locomotion disability and cholinergic defects, e.g., abnormal sensitivities to cholinesterase inhibitors and cholinergic receptor agonists in unc-18 mutants, but Munc-18-3 fails. These data suggest that Munc-18-1 and C. elegans unc-18 may play positive roles in ACh release and that the molecular mechanism of neuronal regulated secretion has been partially conserved from nematodes to mammals.

Key words: neurotransmitter release; unc-18; Caenorhabditis elegans; ACh; transgenic study

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