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 purified alpha subunits of heterotrimeric GTP binding (G) proteins were studied. At sub-anesthetic doses, halothane, isoflurane, enflurane and sevoflurane inhibit exchange of GTPgammaS for GDP bound to Galpha subunits and markedly enhance the dissociation of GTPgammaS, but fail to suppress GDPbetaS release. Nucleotide exchange from non-myristoylated Galpha(i1) is similarly inhibited in the absence of any membrane lipid or detergent. The degrees of inhibition of GDP/GTPgammaS exchange and enhancement of GTPgammaS dissociation are in the same order: alpha(i2)alpha(i1)alpha(i3)alpha(s). By contrast, Galpha(o), which is closely related to Galpha(i), is 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/Mg(2+) bound state of some, but not all Galpha subunits. By destabilizing this state, volatile agents may uncouple metabotropic and other heptahelical receptors from pathways modulating neuronal excitation.