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J Biol Chem, Vol. 274, Issue 9, 5491-5498, February 26, 1999

A Novel Ubiquitously Expressed -Latrotoxin Receptor Is a Member of the CIRL Family of G-protein-coupled Receptors

Konstantin Ichtchenko, Mary A. Bittner^¶, Valery Krasnoperov, Alvin R. Little, Oleg Chepurny, Ronald W. Holz^¶, and Alexander G. Petrenko

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

Poisoning with -latrotoxin, a neurotoxic protein from black widow spider venom, results in a robust increase of spontaneous synaptic transmission and subsequent degeneration of affected nerve terminals. The neurotoxic action of -latrotoxin involves extracellular binding to its high affinity receptors as a first step. One of these proteins, CIRL, is a neuronal G-protein-coupled receptor implicated in the regulation of secretion. We now demonstrate that CIRL has two close homologs with a similar domain structure and high degree of overall identity. These novel receptors, which we propose to name CIRL-2 and CIRL-3, together with CIRL (CIRL-1) belong to a recently identified subfamily of large orphan receptors with structural features typical of both G-protein-coupled receptors and cell adhesion proteins. Northern blotting experiments indicate that CIRL-2 is expressed ubiquitously with highest concentrations found in placenta, kidney, spleen, ovary, heart, and lung, whereas CIRL-3 is expressed predominantly in brain similarly to CIRL-1. It appears that CIRL-2 can also bind -latrotoxin, although its affinity to the toxin is about 14 times less than that of CIRL-1. When overexpressed in chromaffin cells, CIRL-2 increases their sensitivity to -latrotoxin stimulation but also inhibits Ca²⁺-regulated secretion. Thus, CIRL-2 is a functionally competent receptor of -latrotoxin. Our findings suggest that although the nervous system is the primary target of low doses of -latrotoxin, cells of other tissues are also susceptible to the toxic effects of -latrotoxin because of the presence of CIRL-2, a low affinity receptor of the toxin.

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

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