K(+)-stimulated 45Ca2+ flux into rat neocortical mini-slices is blocked by omega-Aga-IVA and the dual Na+/Ca2+ channel blockers lidoflazine and flunarizine.
High-threshold neuronal voltage-sensitive Ca2+ channels (VSCCs) have been classified into at least three subtypes, including L, N, and P, based on biophysical and pharmacological criteria. We examined K(+)-induced 45Ca2+ flux into rat neocortical mini-slices to determine which of these subtype(s) might be involved in this phenomenon. Neither the L-type Ca2+ channel antagonist isradipine at 10 microM nor the N-type antagonist omega-conotoxin GVIA at 1 microM were effective antagonists of 45Ca2+ flux in this model. However, the P-type Ca2+ channel antagonist, omega-Aga-IVA, blocked 70% of flux at 200 nM, with an IC50 of 17 nM, strongly implicating P-type Ca2+ channel involvement in K(+)-stimulated Ca2+ entry into mammalian nerve terminals. About 30% of the flux response was resistant to the action of omega-Aga-IVA, suggesting that a still uncharacterized subtype of VSCC is involved in Ca2+ entry into mammalian nerve terminals. Both the omega-Aga-IVA sensitive and insensitive components of 45Ca2+ flux were blocked by the diphenylalkylpiperazines, lidoflazine and flunarizine (IC50 = 6.4 microM and 11 microM, respectively), which have dual Na+/Ca2+ channel blocking actions.
Geer
J J
JJ
Department of Neuroscience, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48106-1047.
Dooley
D J
DJ
Adams
M E
ME
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002132:Calcium Radioisotopes; D002413:Cations, Divalent / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004594:Electrophysiology; D005444:Flunarizine / Q000494:pharmacology; D066298:In Vitro Techniques; D008013:Lidoflazine / Q000494:pharmacology; D008297:Male; D011188:Potassium / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013111:Spider Venoms / Q000494:pharmacology*; D013268:Stimulation, Chemical; D020867:omega-Agatoxin IVA
D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D002413:Cations, Divalent; D015222:Sodium Channels; D013111:Spider Venoms; D020867:omega-Agatoxin IVA; D008013:Lidoflazine; D005444:Flunarizine; D011188:Potassium; D002118:Calcium