TY - JOUR T1 - Mechanisms and Functional Significance of Inhibition of Neuronal T-Type Calcium Channels by Isoflurane JF - Molecular Pharmacology JO - Mol Pharmacol SP - 542 LP - 554 DO - 10.1124/mol.108.051664 VL - 75 IS - 3 AU - Peihan Orestes AU - Damir Bojadzic AU - Robert M. Chow AU - Slobodan M. Todorovic Y1 - 2009/03/01 UR - http://molpharm.aspetjournals.org/content/75/3/542.abstract N2 - Previous data have indicated that T-type calcium channels (low-voltage activated T-channels) are potently inhibited by volatile anesthetics. Although the interactions of T-channels with a number of anesthetics have been described, the mechanisms by which these agents modulate channel activity, and the functional consequences of such interactions, are not well studied. Here, we used patch-clamp recordings to explore the actions of a prototypical volatile anesthetic, isoflurane (Iso), on recombinant human CaV3.1 and CaV3.2 isoforms of T-channels. We also performed behavioral testing of anesthetic endpoints in mice lacking CaV3.2. Iso applied at resting channel states blocked current through both isoforms in a similar manner at clinically relevant concentrations (1 minimum alveolar concentration, MAC). Inhibition was more prominent at depolarized membrane potentials (-65 versus -100 mV) as evidenced by hyperpolarizing shifts in channel availability curves and a 2.5-fold decrease in IC50 values. Iso slowed recovery from inactivation and enhanced deactivation in both CaV3.1 and CaV3.2 in a comparable manner but caused a depolarizing shift in activation curves and greater use-dependent block of CaV3.2 channels. In behavioral tests, CaV3.2 knockout (KO) mice showed significantly decreased MAC in comparison with wild-type (WT) litter mates. KO and WT mice did not differ in loss of righting reflex, but mutant mice displayed a delayed onset of anesthetic induction. We conclude that state-dependent inhibition of T-channel isoforms in the central and peripheral nervous systems may contribute to isoflurane's important clinical effects. The American Society for Pharmacology and Experimental Therapeutics ER -