A novel ubiquitously expressed alpha-latrotoxin receptor is a member of the CIRL family of G-protein-coupled receptors.

Abstract

Poisoning with alpha-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 alpha-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 alpha-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 alpha-latrotoxin stimulation but also inhibits Ca2+-regulated secretion. Thus, CIRL-2 is a functionally competent receptor of alpha-latrotoxin. Our findings suggest that although the nervous system is the primary target of low doses of alpha-latrotoxin, cells of other tissues are also susceptible to the toxic effects of alpha-latrotoxin because of the presence of CIRL-2, a low affinity receptor of the toxin.

• Authors: K Ichtchenko, M A Bittner, V Krasnoperov, A R Little, O Chepurny, R W Holz, A G Petrenko
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 274 Issue 9 Pg. 5491-8 (Feb 26 1999) ISSN: 0021-9258 [Print] United States
• PMID: 10026162 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Primers
• DNA, Complementary
• Receptors, Peptide
• alpha-latrotoxin receptor
• GTP-Binding Proteins

Topics

• Amino Acid Sequence
• Animals
• Cell Line
• Chromaffin Cells (metabolism)
• Cloning, Molecular
• DNA Primers
• DNA, Complementary
• GTP-Binding Proteins (metabolism)
• Humans
• Molecular Sequence Data
• Protein Binding
• Rats
• Receptors, Peptide (chemistry, genetics, metabolism)
• Sequence Homology, Amino Acid