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Research ArticleArticle

Cav3.2 Channel Is a Molecular Substrate for Inhibition of T-Type Calcium Currents in Rat Sensory Neurons by Nitrous Oxide

Slobodan M. Todorovic, Vesna Jevtovic-Todorovic, Steven Mennerick, Edward Perez-Reyes and Charles F. Zorumski
Molecular Pharmacology September 2001, 60 (3) 603-610;
Slobodan M. Todorovic
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Vesna Jevtovic-Todorovic
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Steven Mennerick
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Edward Perez-Reyes
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Charles F. Zorumski
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Abstract

Although nitrous oxide (N2O; 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 N2O on voltage-gated Ca2+ channels in acutely dissociated small sensory neurons of adult rat. At subanesthetic concentrations, N2O blocks low-voltage-activated, T-type Ca2+ currents (T currents), but not high-voltage-activated (HVA) currents. This blockade of T currents was concentration dependent, with an IC50 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 N2O application. The magnitude of T current blockade by N2O 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′-(γ-thio)triphosphate or guanosine 5′-0-(2-thiodiphosphate) suggesting a lack of involvement of G-proteins in the inhibition. N2O selectively blocked currents arising from the Cav3.2 but not Cav3.1 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 Cav3.2 T currents exhibited little voltage- or use-dependence. These data indicate that N2O selectively blocks T-type but not HVA Ca2+ currents in small sensory neurons and Cav3.2 currents in HEK cells at subanesthetic concentrations. Blockade of T currents may contribute to the anesthetic and/or analgesic effects of N2O.

Footnotes

  • These studies were supported by FAER/Abbott Laboratories New Investigator Award (S.M.T.), NIDA Career Development Awards 1KO8-DA00428 (to S.M.T.) and 1KO8-DA00406 (to V.J.T.), NIA Grant P01–11355 (V.J.T.), the Bantly Foundation (C.F.Z.), NIMH Grant R01–45493, NIGMS Grant P01–47969 (C.F.Z.), and NARSAD (S.M.).

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    HVA
    high-voltage-activated
    T-type currents
    T currents
    HEK
    human embryonic kidney
    DRG
    dorsal root ganglion
    CgTx
    conotoxin
    DMSO
    dimethyl sulfoxide
    GTPγs
    guanosine 5′-(γ-thio)triphosphate
    GDPβS
    guanosine 5′-0-(2-thiodiphosphate)
    CNS
    central nervous system
    MAC
    minimum alveolar concentration
    phenytoin
    5,5-diphenylhydantoin
    • Received April 30, 2001.
    • Accepted June 11, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Research ArticleArticle

Cav3.2 Channel Is a Molecular Substrate for Inhibition of T-Type Calcium Currents in Rat Sensory Neurons by Nitrous Oxide

Slobodan M. Todorovic, Vesna Jevtovic-Todorovic, Steven Mennerick, Edward Perez-Reyes and Charles F. Zorumski
Molecular Pharmacology September 1, 2001, 60 (3) 603-610;

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Research ArticleArticle

Cav3.2 Channel Is a Molecular Substrate for Inhibition of T-Type Calcium Currents in Rat Sensory Neurons by Nitrous Oxide

Slobodan M. Todorovic, Vesna Jevtovic-Todorovic, Steven Mennerick, Edward Perez-Reyes and Charles F. Zorumski
Molecular Pharmacology September 1, 2001, 60 (3) 603-610;
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