Inhibition of recombinant low-voltage-activated Ca(2+) channels by the neuroprotective agent BW619C89 (Sipatrigine).
T-type Ca(2+) currents were recorded in 2 mM Ca(2+) from HEK 293 cells stably expressing recombinant low-voltage-activated Ca(2+) channel subunits. Current-voltage relationships revealed that these currents were low-voltage activated in nature and could be reversibly antagonised by mibefradil, a known T-type channel blocker. At a test potential of -25 mV alpha(1I)-mediated Ca(2+) currents were rapidly and reversibly inhibited by 1-100 microM BW619C89 (IC(50)=14 microM, Hill coefficient 1.3). In contrast to its actions on N-type Ca(2+) channels, a near IC(50) dose (10 microM) of BW619C89 produced no alterations in either the kinetics or voltage-dependence of T-type currents. In additional single dose experiments, currents mediated by rat alpha(1G), human alpha(1H) or human alpha(1I) channel subunits were also inhibited by BW619C89. Overall our data indicate that T-type Ca(2+) channels are more potently blocked by BW619C89 than either type-II Na(+) channels or N-type Ca(2+) channels. It seems, therefore, that inhibition of low-voltage-activated Ca(2+) channels is likely to contribute to the anticonvulsant and neuroprotective actions of this and related compounds.
McNaughton
N C
NC
Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, Third Avenue, Harlow, Essex, UK.
Hainsworth
A H
AH
Green
P J
PJ
Randall
A D
AD
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D018696:Neuroprotective Agents; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; D015222:Sodium Channels; C081980:sipatrigine