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J Biol Chem, Vol. 274, Issue 6, 3590-3596, February 5, 1999

Structural Requirements for -Latrotoxin Binding and -Latrotoxin-stimulated Secretion
A STUDY WITH CALCIUM-INDEPENDENT RECEPTOR OF -LATROTOXIN (CIRL) DELETION MUTANTS

Valery Krasnoperov, Mary A. Bittner^§, Ronald W. Holz^§, Oleg Chepurny, and Alexander G. Petrenko^¶

From the  Departments of Pharmacology, ^¶ Physiology and Neuroscience, and ^¶ Environmental Medicine, New York University Medical Center, New York, New York 10016 and the ^§ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Stimulation of neurotransmitter release by -latrotoxin requires its binding to the calcium-independent receptor of -latrotoxin (CIRL), an orphan neuronal G protein-coupled receptor. CIRL consists of two noncovalently bound subunits, p85, a heptahelical integral membrane protein, and p120, a large extracellular polypeptide with domains homologous to lectin, olfactomedin, mucin, the secretin receptor family, and a novel structural motif common for large orphan G protein-coupled receptors. The analysis of CIRL deletion mutants indicates that the high affinity -latrotoxin-binding site is located within residues 467-891, which comprise the first transmembrane segment of p85 and the C-terminal half of p120. The N-terminal lectin, olfactomedin, and mucin domains of p120 are not required for the interaction with -latrotoxin. Soluble p120 and all its fragments, which include the 467-770 residues, bind -latrotoxin with low affinity suggesting the importance of membrane-embedded p85 for the stabilization of the complex of the toxin with p120. Two COOH-terminal deletion mutants of CIRL, one with the truncated cytoplasmic domain and the other with only one transmembrane segment left of seven, supported both -latrotoxin-induced calcium uptake in HEK293 cells and -latrotoxin-stimulated secretion when expressed in chromaffin cells, although with a different dose dependence than wild-type CIRL and its N-terminal deletion mutant. Thus the signaling domains of CIRL are not critically important for the stimulation of exocytosis in intact chromaffin cells by -latrotoxin.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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