G-protein activation decreases isoflurane inhibition of N-type Ba2+ currents.
BACKGROUND
G-protein activation mediates inhibition of N-type Ca2+ currents. Volatile anesthetics affect G-protein pathways at various levels, and activation of G-proteins has been shown to increase the volatile anesthetic potency for inhibiting the electrical-induced contraction in ileum. The authors investigated whether isoflurane inhibition of N-type Ba2+ currents was mediated by G-protein activation.


METHODS
N-type Ba2+ currents were measured in the human neuronal SH-SY5Y cell line by using the whole cell voltage-clamp method.


RESULTS
Isoflurane was found to have two effects on N-type Ba2+ currents. First, isoflurane reduced the magnitude of N-type Ba2+ currents to a similar extent (IC50 approximately 0.28 mm) in the absence and presence of GDPbetaS (a nonhydrolyzable GDP analog). Interestingly, GTPgammaS (a nonhydrolyzable GTP analog and G-protein activator) in a dose-dependent manner reduced the isoflurane block; 120 microm GTPgammaS completely eliminated the block of 0.3 mm isoflurane and reduced the apparent isoflurane potency by approximately 2.4 times (IC50 approximately 0.68 mm). Pretreatment with pertussis toxin or cholera toxin did not eliminate the GTPgammaS-induced protection against the isoflurane block. Furthermore, isoflurane reduced the magnitude of voltage-dependent G-protein-mediated inhibition of N-type Ba2+ currents, and this effect was eliminated by pretreatment with pertussis toxin or cholera toxin.


CONCLUSIONS
It was found that activation of G-proteins in a neuronal environment dramatically reduced the isoflurane potency for inhibiting N-type Ba2+ currents and, in turn, isoflurane affected the G-protein regulation of N-type Ba2+ currents.
Nikonorov
Igor M
IM
Anesthesiology Department, New York University School of Medicine, New York, New York 10016, USA.
Blanck
Thomas J J
TJ
Recio-Pinto
Esperanza
E
D000465:Algorithms; D001464:Barium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D018118:Chloride Channels / Q000378:metabolism; D002772:Cholera Toxin / Q000494:pharmacology; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D018118:Chloride Channels; D011963:Receptors, GABA-A; D001464:Barium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002772:Cholera Toxin; D007530:Isoflurane; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins