Pharmacology of recombinant low-voltage activated calcium channels.

Several types of voltage- or ligand-activated calcium channels contribute to the excitability of neuronal cells. Low-voltage-activated (LVA), T-type calcium channels are characterised by relatively negative threshold of activation and therefore they can generate low-threshold spikes, which are essential for burst firing. At least three different proteins form T-type calcium current in neurons: Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3. Expression of these proteins in various brain regions is complementary. Individual channel types could be distinguished by different sensitivity towards inorganic cations. This inhibition can contribute to the toxicity of some heavy metals. Selective inhibition of T-type calcium channels by organic blockers may have clinical importance in some forms of epilepsy. Mibefradil inhibits the expressed Ca(v2)3.1, Ca(v)3.2 and Ca(v)3.3 channels in nanomolar concentrations with Ca(v)3.3 channel having lowest affinity. The sensitivity of the expressed Ca(v)3.1 channel to the antiepileptic drugs, valproate and ethosuximide, is low. Ca(v)3.1 channel is moderately sensitive to phenytoin. The Ca(v)3.2 channel is sensitive to ethosuximide, amlodipine and amiloride. All three LVA calcium channels are moderately sensitive to active metabolites of methosuximide, i.e. alpha-methyl-alpha-phenylsuccinimide. Several neuroleptics inhibit all three LVA channels in clinically relevant concentrations. All three channels are also inhibited by the endogenous cannabinoid anandamide. A high affinity peptide blocker for these Ca channels is the scorpion toxin kurtoxin which inhibits the Ca(v)3.1 and Ca(v)3.2, but not the Ca(v)3.3 channel in nanomolar concentrations. Nitrous oxide selectively inhibits the Ca(v)3.2, but not the Ca(v)3.1 channel. The Ca(v)3.2, but not the Ca(v)3.1 channel is potentiated by stimulation of Ca(2+)/CaM-dependent protein kinase.