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J Biol Chem. 2017 Dec 8;292(49):19989-19998. doi: 10.1074/jbc.M117.800698. Epub 2017 Oct 17.

Development of novel biosensors to study receptor-mediated activation of the G-protein α subunits Gs and Golf.

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From the National Institute on Drug Abuse, Baltimore, Maryland 21224,
the Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
From the National Institute on Drug Abuse, Baltimore, Maryland 21224.
the Departments of Psychiatry and Pharmacology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, and
the Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032.


s (Gs) and Gαolf (Golf) are highly homologous G-protein α subunits that activate adenylate cyclase, thereby serving as crucial mediators of intracellular signaling. Because of their dramatically different brain expression patterns, we studied similarities and differences between their activation processes with the aim of comparing their receptor coupling mechanisms. We engineered novel luciferase- and Venus-fused Gα constructs that can be used in bioluminescence resonance energy transfer assays. In conjunction with molecular simulations, these novel biosensors were used to determine receptor activation-induced changes in conformation. Relative movements in Gs were consistent with the crystal structure of β2 adrenergic receptor in complex with Gs Conformational changes in Golf activation are shown to be similar to those in Gs Overall the current study reveals general similarities between Gs and Golf activation at the molecular level and provides a novel set of tools to search for Gs- and Golf-specific receptor pharmacology. In view of the wide functional and pharmacological roles of Gs- and Golf-coupled dopamine D1 receptor and adenosine A2A receptor in the brain and other organs, elucidating their differential structure-function relationships with Gs and Golf might provide new approaches for the treatment of a variety of neuropsychiatric disorders. In particular, these novel biosensors can be used to reveal potentially therapeutic dopamine D1 receptor and adenosine A2A receptor ligands with functionally selective properties between Gs and Golf signaling.


G protein; G-protein–coupled receptor (GPCR); bioluminescence resonance energy transfer (BRET); dopamine receptor; pharmacology

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