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

• Published in: European journal of pharmacology 1999-11, Vol.384 (2), p.213-222
• Main Authors: Pentyala, Srinivas N., Sung, Ki-Young, Chowdhury, Ahmed, Rebecchi, Mario J.
• Format: Article
• Language: English
• Subjects: Anesthetic volatile; Anesthetics, Inhalation - pharmacology; Anesthetics. Neuromuscular blocking agents; Biological and medical sciences; Dose-Response Relationship, Drug; G-protein; GTP-Binding Proteins - chemistry; GTP-Binding Proteins - metabolism; Guanine nucleotide; Guanine Nucleotides - chemistry; Guanine Nucleotides - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - chemistry; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Guanosine Diphosphate - chemistry; Guanosine Diphosphate - metabolism; Guanosine Triphosphate - chemistry; Guanosine Triphosphate - metabolism; Gα subunit; Halothane - pharmacology; Kinetics; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Protein Binding - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(99)00625-1

The effects of volatile anesthetics on guanine nucleotide binding to the purified α subunits of heterotrimeric GTP binding (G) proteins were studied. At sub-anesthetic doses, halothane, isoflurane, enflurane and sevoflurane inhibit exchange of GTPγS for GDP bound to Gα subunits and markedly enhance the dissociation of GTPγS, but fail to suppress GDPβS release. Nucleotide exchange from non-myristoylated Gα i1 is similarly inhibited in the absence of any membrane lipid or detergent. The degrees of inhibition of GDP/GTPγS exchange and enhancement of GTPγS dissociation are in the same order: α i2>α i1>α i3>α s. By contrast, Gα o, which is closely related to Gα 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 Gα subunits. By destabilizing this state, volatile agents may uncouple metabotropic and other heptahelical receptors from pathways modulating neuronal excitation.