Inhibition of alpha(1E) Ca(2+) channels by carbonic anhydrase inhibitors.
We examined if a range of carbonic anhydrase inhibitors (CAIs) interacted with the high-voltage activated voltage-sensitive calcium channels (VSCCs) encoded by the human alpha(1E) subunit. Whole-cell recordings were made from HEK293 cells stably expressing human alpha(1E)beta(3)-mediated calcium channels. SNX-482 (an alpha(1E) inhibitor) blocked alpha(1E)-mediated VSCCs with an IC(50) close to 10 nM. The anticonvulsant CAI ethoxyzolamide also inhibited these currents, with an IC(50) close to 1 microM, and produced an accompanying 20-mV hyperpolarizing shift in the steady-state inactivation profile. Other structurally diverse CAIs (e.g., acetazolamide and benzolamide) produced approximately 30 - 40% inhibition of alpha(1E)beta(3)-mediated Ca(2+) currents at 10 microM. Topiramate (10 microM), an anticonvulsant with CAI activity, inhibited these currents by 68 +/- 7%. This off-target activity of CAIs at VSCCs may contribute to some of the effects they produce both in vitro and in vivo.
McNaughton
Nicolle C L
NC
Neurology and GI CEDD, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, UK.
Davies
Ceri H
CH
Randall
Andrew
A
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D020908:Calcium Channels, R-Type / Q000187:drug effects / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004594:Electrophysiology; D005016:Ethoxzolamide / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins; D013111:Spider Venoms / Q000494:pharmacology
C423009:CACNA1E protein, human; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020908:Calcium Channels, R-Type; D002257:Carbonic Anhydrase Inhibitors; D027682:Cation Transport Proteins; D011994:Recombinant Proteins; C115521:SNX 482; D013111:Spider Venoms; D005016:Ethoxzolamide