Ca(v)3.2 channel is a molecular substrate for inhibition of T-type calcium currents in rat sensory neurons by nitrous oxide.
Although nitrous oxide (N(2)O; laughing gas) remains widely used as an anesthetic and analgesic in clinical practice, its cellular mechanisms of action remain inadequately understood. In this report, we examined the effects of N(2)O on voltage-gated Ca(2+) channels in acutely dissociated small sensory neurons of adult rat. At subanesthetic concentrations, N(2)O blocks low-voltage-activated, T-type Ca(2+) currents (T currents), but not high-voltage-activated (HVA) currents. This blockade of T currents was concentration dependent, with an IC(50) value of 45 +/- 13%, maximal block of 38 +/- 12%, and Hill coefficient of 2.6 +/- 1.0. No desensitization of the response or change in current kinetics was observed during N(2)O application. The magnitude of T current blockade by N(2)O does not seem to reflect any use- or voltage-dependent properties. In addition, T current blockade was not altered when intracellular GTP was replaced with guanosine 5'-(gamma-thio)triphosphate or guanosine 5'-0-(2-thiodiphosphate) suggesting a lack of involvement of G-proteins in the inhibition. N(2)O selectively blocked currents arising from the Ca(v)3.2 but not Ca(v)3.1 recombinant channels stably expressed in human embryonic kidney (HEK) cells in a concentration-dependent manner with an apparent affinity and potency similar to native dorsal root ganglion currents. Analogously, the block of Ca(v)3.2 T currents exhibited little voltage- or use-dependence. These data indicate that N(2)O selectively blocks T-type but not HVA Ca(2+) currents in small sensory neurons and Ca(v)3.2 currents in HEK cells at subanesthetic concentrations. Blockade of T currents may contribute to the anesthetic and/or analgesic effects of N(2)O.
Todorovic
S M
SM
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Jevtovic-Todorovic
V
V
Mennerick
S
S
Perez-Reyes
E
E
Zorumski
C F
CF
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004594:Electrophysiology; D006801:Humans; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D009609:Nitrous Oxide / Q000494:pharmacology*; D051381:Rats; D014162:Transfection
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D009609:Nitrous Oxide