Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes.
The genes encoding the alpha(1A), alpha(1B), alpha(1C) and alpha(1E) subunits of neuronal high voltage-gated Ca channels (HVGCCs) were separately expressed with beta(1B) and alpha(2)/delta subunits in Xenopus oocytes to determine the effects of volatile anesthetics (VAs) on currents through each specific channel. VA effects were determined on currents carried by Ba(2+) (I(Ba)) using the two electrode voltage clamp technique. Although time to peak was unaffected, both halothane (0.59 mM) and isoflurane (0.70 mM) reversibly inhibited peak I(Ba) by 25-35% and late current (at 830 ms) by 50-60%. A hyperpolarizing shift in steady-state inactivation of alpha(1E)-current was found which could contribute up to one third of observed decrease in the peak current. The rate of inactivation of I(Ba) seen with alpha(1A), alpha(1B) and alpha(1E)-type Ca channels was consistently increased by halothane and isoflurane. To more clearly quantify these effects, I(Ba) inactivation was fit by a single exponential function. The anesthetics depressed both the inactivating and non-inactivating residual components of I(Ba) and decreased the time constant of inactivation. In the case of I(Ba) through alpha(1C)-type channels, inactivation was minimal; however, the average current was inhibited by VAs. Similar inhibition of all these HVGCCs by halothane and isoflurane suggests that a common structural component may be involved. Furthermore, the inhibition of such neuronal HVGCCs in situ could alter synaptic neurotransmitter release and contribute to the anesthetic state.
Kamatchi
G L
GL
Department of Anesthesiology, University of Virginia Health Sciences Center, PO Box 10010, Charlottesville, VA 22906-0010, USA.
Chan
C K
CK
Snutch
T
T
Durieux
M E
ME
Lynch
C
C
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D007530:Isoflurane / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes; D018408:Patch-Clamp Techniques; D014835:Volatilization; D014982:Xenopus laevis
D018685:Anesthetics, Inhalation; D002121:Calcium Channel Blockers; D007530:Isoflurane; D006221:Halothane