High affinity block of myocardial L-type calcium channels by the spider toxin omega-Aga-toxin IIIA: advantages over 1,4-dihydropyridines.
The peptide omega-agatoxin IIIA (omega-Aga-IIIA) from venom of the funnel web spider Agelenopsis aperta blocks L-type Ca2+ channels in neurons and myocardial cells with high affinity. We report that omega-Aga-IIIA also blocks whole-cell Ca2+ channel currents in guinea pig atrial myocytes. Although other high affinity blockers of L-type Ca2+ channels are available (such as the 1,4-dihydropyridines), omega-Aga-IIIA is a valuable pharmacological tool; omega-Aga-IIIA is the only known ligand that blocks L-type Ca2+ channels with high affinity at all voltages (IC50 approximately 1 nM) and it causes little or no block of T-type Ca2+ channels, unlike the 1,4-dihydropyridines. We use omega-Aga-IIIA to selectively eliminate L-type Ca2+ currents and we show that felodipine blocks T-type Ca2+ currents. Consequently, the toxin is better than dihydropyridines for separating ionic currents through voltage-dependent Ca2+ channels and defining their physiological function.
Cohen
C J
CJ
Department of Membrane Biochemistry and Biophysics, Merck Research Laboratories, Rahway, New Jersey 07065.
Ertel
E A
EA
Smith
M M
MM
Venema
V J
VJ
Adams
M E
ME
Leibowitz
M D
MD
D060848:Agatoxins; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D015736:Felodipine / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D013111:Spider Venoms / Q000494:pharmacology*; D013379:Substrate Specificity
D060848:Agatoxins; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D013111:Spider Venoms; C070132:omega-agatoxin III; C038806:1,4-dihydropyridine; D015736:Felodipine