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Linking receptor activation to changes in Sw I and II of G? proteins.

ABSTRACT: G-protein coupled receptors catalyze nucleotide exchange on G proteins, which results in subunit dissociation and effector activation. In the recent ?2AR-Gs structure, portions of Switch I and II of G? are not fully elucidated. We paired fluorescence studies of receptor-G?i interactions with the ?2AR-Gs and other Gi structures to investigate changes in Switch I and II during receptor activation and GTP binding. The ?2/?3 loop containing Leu194 of G?i is located between Switches I and II, in close proximity to IC2 of the receptor and the C-terminus of G?, thus providing an allosteric connection between these Switches and receptor activation. We compared the environment of residues in myristoylated G?i proteins in the heterotrimer to that upon receptor activation and subsequent GTP binding. Upon receptor activation, residues in both Switch regions are less solvent-exposed, as compared to the heterotrimer. Upon GTP?S binding, the environment of several residues in Switch I resemble the receptor-bound state, while Switch II residues display effects on their environment which are consistent with their role in GTP binding and G?? dissociation. The ability to merge available crystal structures with solution studies is a powerful tool to gain insight into conformational changes associated with receptor-mediated Gi protein activation.

SUBMITTER: Hamm HE

PROVIDER: S-EPMC3726552 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Linking receptor activation to changes in Sw I and II of Gα proteins.

Hamm Heidi E HE Kaya Ali I AI Gilbert James A JA Preininger Anita M AM

Journal of structural biology 20130304 1

G-protein coupled receptors catalyze nucleotide exchange on G proteins, which results in subunit dissociation and effector activation. In the recent β2AR-Gs structure, portions of Switch I and II of Gα are not fully elucidated. We paired fluorescence studies of receptor-Gαi interactions with the β2AR-Gs and other Gi structures to investigate changes in Switch I and II during receptor activation and GTP binding. The β2/β3 loop containing Leu194 of Gαi is located between Switches I and II, in clos ...[more]

PMID: 23466875

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Project description:GPCR-Gi protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-Gi protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. In gastric smooth muscle, there are two muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3. M2 receptor activates the muscarinic receptor-operated nonselective cationic current (mIcat, NSCC(ACh)) and induces positive chronotropic effect. Meanwhile, M3 receptor induces hydrolysis of PIP2 and releases DAG and IP3. This IP3 increases intracellular Ca2+ and then leads to contraction of GI smooth muscles. The activation of mIcat is inhibited by anti-Gi/o protein antibodies in GI smooth muscle, indicating the involvement of Gαi/o protein in the activation of mIcat. TRPC4 channel is a molecular candidate for mIcat and can be directly activated by constitutively active Gαi QL proteins. TRPC4 and TRPC5 belong to the same subfamily and both are activated by Gi/o proteins. Initial studies suggested that the binding sites for G protein exist at the rib helix or the CIRB domain of TRPC4/5 channels. However, recent cryo-EM structure showed that IYY58-60 amino acids at ARD of TRPC5 binds with Gi3 protein. Considering the expression of TRPC4/5 in the brain, the direct G protein activation on TRPC4/5 is important in terms of neurophysiology. TRPC4/5 channels are also suggested as a coincidence detector for Gi and Gq pathway as Gq pathway increases intracellular Ca2+ and the increased Ca2+ facilitates the activation of TRPC4/5 channels. More complicated situation would occur when GIRK, KCNQ2/3 (IM) and TRPC4/5 channels are co-activated by stimulation of muscarinic receptors at the acetylcholine-releasing nerve terminals. This review highlights the effects of GPCR-Gi protein pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, on various oragns, and it emphasizes the importance of considering TRPC4/5 channels as crucial players in the field of neuroscience.

Dataset Information

Linking receptor activation to changes in Sw I and II of G? proteins.

Publications

Linking receptor activation to changes in Sw I and II of Gα proteins.

Similar Datasets

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