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

被引:85
作者
Ichtchenko, K
Bittner, MA
Krasnoperov, V
Little, AR
Chepurny, O
Holz, RW
Petrenko, AG
机构
[1] NYU, Med Ctr, Dept Pharmacol, New York, NY 10016 USA
[2] NYU, Med Ctr, Dept Physiol & Neurosci, New York, NY 10016 USA
[3] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA
[4] NYU, Med Ctr, Dept Environm Med, New York, NY 10016 USA
关键词
D O I
10.1074/jbc.274.9.5491
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, GIRL, is a neuronal G-protein-coupled receptor implicated in the regulation of secretion. We now demonstrate that GIRL 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.
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页码:5491 / 5498
页数:8
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