ALPHA-LATROTOXIN STIMULATES EXOCYTOSIS BY THE INTERACTION WITH A NEURONAL G-PROTEIN-COUPLED RECEPTOR

alpha-Latrotoxin is a potent stimulator of neurosecretion. Its action requires extracellular binding to high affinity presynaptic receptors. Neurexin I alpha was previously described as a high affinity alpha-la trotoxin receptor that binds the toxin only in the presence of calcium ions. Therefore, the interaction of alpha-latrotoxin with neurexin I alpha cannot explain how alpha-latrotoxin stimulates neurotransmitter release in the absence of calcium. We describe molecular cloning and f unctional expression of the calcium-independent receptor of alpha-latr otoxin (GIRL), which is a second high affinity alpha-latrotoxin recept or that may be the major mediator of alpha-latrotoxin's effects. GIRL appears to be a novel orphan G-protein-coupled receptor, a member of t he secretin receptor family. In contrast with other known serpentine r eceptors, GIRL has two subunits of the 120 and 85 kDa that are the res ult of endogenous proteolytic cleavage of a precursor polypeptide. GIR L is found in brain where it is enriched in the striatum and cortex. E xpression of GIRL in chromaffin cells increases the sensitivity of the cells to the effects of alpha-latrotoxin, demonstrating that this pro tein is functional in coupling to secretion. Syntaxin, a component of the fusion complex, copurifies with GIRL on an alpha-latrotoxin affini ty column and forms stable complexes with this receptor in vitro. Inte raction of GIRL with a specific presynaptic neurotoxin and with a comp onent of the docking-fusion machinery suggests its role in regulation of neurosecretion.