Volatile anesthetics modulate the binding of guanine nucleotides to the alpha subunits of heterotrimeric GTP binding proteins

The effects of volatile anesthetics on guanine nucleotide binding to the pu rified or subunits of heterotrimeric GTP binding (G) proteins were studied. At sub-anesthetic doses, halothane, isoflurane, enflurane and sevoflurane inhibit exchange of GTP gamma S for GDP bound to G alpha. subunits and mark edly enhance the dissociation of GTP gamma S, but fail to suppress GDP beta S release. Nucleotide exchange from non-myristoylated G alpha(i1), is simi larly inhibited in the absence of any membrane lipid or detergent. The degr ees of inhibition of GDP/GTP gamma S exchange and enhancement of GTP gamma S dissociation are in the same order: alpha(i2) > alpha(i1) > alpha(i3) > a lpha(s). By contrast, G alpha(o), which is closely related to G alpha(i), i s completely insensitive to anesthetics. We conclude that volatile agents, at clinically relevant doses, have a direct effect on the conformation and stability of the GTP/Mg2+ bound state of some, but not all G alpha subunits . By destabilizing this state, volatile agents may uncouple metabotropic an d other heptahelical receptors from pathways modulating neuronal excitation . (C) 1999 Elsevier Science B.V. All rights reserved.