Modulation of calcium current by calmodulin antagonists.
The short-term effects of bath applied calmodulin antagonists--chlorpromazine, trifluoperazine and calmidazolium (R24571)--on potential-dependent calcium channels in the membrane of intracellularly perfused snail neurons were studied in voltage clamp conditions. All the drugs affected the calcium inward current peak value, the effects being reversible and dependent on the concentration used. Submicromolar concentrations (0.1-1 microM) increased the current amplitude (the maximal effect was on the average 20% at 0.5 microM), whereas higher concentrations inhibited the current. Analysis of the dose-effect curve for the blockade suggests positive cooperativity in the interaction of the drugs with the channel; experimental data on chlorpromazine action (10-100 microM) are well approximated by a binding curve for two molecules with the effective Kd = 70 microM. The efficiency of the blockade depended neither on the current-carrying cations (calcium or barium) nor on the intracellular introduction of 10 mM EGTA. The presence of calmodulin antagonists influenced the blockade of the calcium current by inorganic blockers: 50 microM chlorpromazine decreased the Kd value from 90 to 50 microM for the current blockade by Cd ions. It is suggested that calmodulin antagonists interact with two sites in the calcium channel, with high and low binding affinity (responsible for enhancement and inhibition of the current, respectively). The interaction induces changes in binding of penetrating cations in the channel, thereby producing modulation of the calcium current amplitude.
Doroshenko
P A
PA
A.A. Bogomoletz Institute of Physiology, Kiev, U.S.S.R.
Kostyuk
P G
PG
Luk'yanetz
E A
EA
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology*; D002746:Chlorpromazine / Q000494:pharmacology*; D006372:Helix, Snails / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D014268:Trifluoperazine / Q000494:pharmacology*
D015220:Calcium Channels; D002147:Calmodulin; D007093:Imidazoles; D014268:Trifluoperazine; C031938:calmidazolium; D002746:Chlorpromazine