Toxityping rat brain calcium channels with omega-toxins from spider and cone snail venoms.
Different types of voltage-sensitive Ca2+ channels in the brain can be defined by specific ligands: L-type Ca2+ channels are uniquely sensitive to dihydropyridines, and N-type Ca2+ channels are selectively blocked by the Conus peptide omega-CTX-GVIA. Cloning data have revealed additional calcium channel types in mammalian brain for which selective ligands would be desirable. We describe binding experiments involving three newer ligands that block dihydropyridine- and omega-CTX-GVIA-resistant Ca channels: omega-Aga-IIIA and omega-Aga-IVA from venom of the spider Agelenopsis aperta and omega-CTX-MVIIC from Conus magus. [125I]omega-Aga-IVA binds with high affinity (IC50 = approximately 50 nM) to receptors in rat brain which may correspond to P-like calcium channels. A second high-affinity site (IC50 = approximately 1 nM) is defined by [125I]omega-CTX-MVIIC, proposed here to be on an "O"-type calcium channel. [125I]omega-Aga-IIIA targets homologous binding sites present on multiple Ca channel types. The IIIA sites overlap with the binding sites for [125I]omega-CTX-GVIA and [125I]omega-CTX-MVIIC. The IIIA sites do not overlap with the site defined by omega-Aga-IVA. Thus toxin ligands may be highly specific for a particular Ca channel (i.e., GVIA for the N-type channel) or exhibit broader specificity (i.e., omega-Aga-IIIA, which appears to bind L-, N-, P-, and O-type Ca2+ channels).
Adams
M E
ME
Department of Entomology, University of California, Riverside 92521.
Myers
R A
RA
Imperial
J S
JS
Olivera
B M
BM
D060848:Agatoxins; D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000145:classification* / Q000187:drug effects; D007457:Iodine Radioisotopes; D008024:Ligands; D008978:Mollusk Venoms / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012908:Snails; D013111:Spider Venoms / Q000302:isolation & purification / Q000494:pharmacology*; D013112:Spiders; D013574:Synaptosomes / Q000378:metabolism; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins
D060848:Agatoxins; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007457:Iodine Radioisotopes; D008024:Ligands; D008978:Mollusk Venoms; D010455:Peptides; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; D020960:omega-Conotoxins; C070132:omega-agatoxin III; C075851:omega-conotoxin-MVIIC; D002118:Calcium