Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins.
The unc-13 gene in Caenorhabditis elegans is essential for normal presynaptic function and encodes a large protein with C1- and C2-domains. In protein kinase C and synaptotagmin, C1- and/or C2-domains are regulatory domains for Ca2+, phospholipids, and diacylglycerol, suggesting a role for unc-13 in regulating neurotransmitter release. To determine if a similar protein is a component of the presynaptic machinery for neurotransmitter release in vertebrates, we studied unc-13 homologues in rat. Molecular cloning revealed that three homologues of unc-13 called Munc13-1, -13-2, and -13-3 are expressed in rat brain. Munc13s are large, brain-specific proteins with divergent N termini but conserved C termini containing C1- and C2-domains. Specific antibodies demonstrated that Munc13-1 is a peripheral membrane protein that is enriched in synaptosomes and localized to plasma membranes but absent from synaptic vesicles. Our data suggest that the function of unc-13 in C. elegans is conserved in mammals and that Munc13s act as plasma membrane proteins in nerve terminals. The presence of C1- and C2-domains in these proteins and the phenotype of the C. elegans mutants raise the possibility that Munc13s may have an essential signaling role during neurotransmitter release.
Brose
N
N
Department of Molecular Genetics, University of Texas Southwestern Medical School, Dallas 75235, USA.
Hofmann
K
K
Hata
Y
Y
Südhof
T C
TC
D000595:Amino Acid Sequence; D000818:Animals; D029742:Caenorhabditis elegans Proteins; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins; D015801:Helminth Proteins / Q000032:analysis / Q000737:chemistry* / Q000235:genetics; D008565:Membrane Proteins / Q000032:analysis; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D013570:Synaptic Membranes / Q000737:chemistry
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D010743:Phospholipids; C083141:phorbol ester binding protein; D002118:Calcium