A murine neural-specific homolog corrects cholinergic defects in Caenorhabditis elegans unc-18 mutants

Keiko Gengyo-Ando, Hitoshi Kitayama, Masahiro Mukaida, Yoji Ikawa

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

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 isoforms-neural 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.

Original languageEnglish
Pages (from-to)6695-6702
Number of pages8
JournalJournal of Neuroscience
Volume16
Issue number21
DOIs
Publication statusPublished - 1996 Nov 1

Keywords

  • ACh
  • Caenorhabditis elegans
  • neurotransmitter release
  • transgenic study
  • unc-18

ASJC Scopus subject areas

  • Neuroscience(all)

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