Contrasting the effects of nifedipine on subtypes of endogenous and recombinant T-type Ca2+ channels

There is evidence that nifedipine (Nif) - a dihydropyridine (DHP) Ca2+ -channel antagonist mostly known for its L-type-specific action -is capable of blocking low voltage-activated (LVA or T-type) Ca2+ channels as well. However, the discrimination by Nif of either various endogenous T-channel subtypes, evident from functional studies, or cloned Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3 T-channel alpha 1 subunits have not been determined. Here, we investigated the effects of Nif on currents induced by Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3 expression in Xenopus oocytes or HEK-293 cells (I-1alphaG, I-alpha1H and I-alpha1I, respectively) and two kinetically distinct, fast and slow, LVA currents in thalamic neurons (I-LVA.f and I-LVA.s). At voltages of the maximums of respective currents the drug most potently blocked I-alpha1H (IC50 = 5 muM, max block 41 %) followed by I-alpha1G (IC50 = 109 muM, 23 %) and 1, 11 (IC50 = 243 muM, 47%). The mechanism of blockade included interaction with Ca(v)3. 1, Ca(v)3.2 and Ca(v)3.3 open and inactivated states. Nif blocked thalamic I-LVA,I-f and I-LVA,I-s with nearly equal potency (IC50 = 22 muM and 28 muM, respectively),but with different maximal inhibition (8 1 % and 5 1 %, respectively). We conclude that Ca(v)3.2 is the most sensitive to Nif, and that quantitative characteristics of drug action on T-type Ca2+ channels depend on cellular system they are expressed in. Some common features in the voltage-and state-dependence of Nif action on endogenous and recombinant currents together with previous data on T-channel alpha1 subunits mRNA expression patterns in the thalamus point to Ca(v)3.1 and Ca(v)3.3 as the major contributors to thalamic I-LVA,I-f and I-LvA,I-s respectively. (C) 2004 Elsevier Inc. All rights reserved.