Revealing the plasma membrane in GPCR signaling

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Science Signaling  16 Jun 2020:
Vol. 13, Issue 636, eabd3019
DOI: 10.1126/scisignal.abd3019

The structure of a membrane-embedded, activated D2 dopamine receptor will help in the development of more selective therapeutics.

The neurotransmitter dopamine acts through a family of five G protein–coupled receptors (GPCRs), D1R to D5R, to mediate physiological and cognitive functions, including reward and movement. Agonists of the D2 dopamine receptor (D2R) are used to treat Parkinson’s disease (PD), whereas D2R inhibitors reduce dopaminergic signaling to treat schizophrenia. D2R couples to the Gi family of G proteins to inhibit production of the second messenger cAMP. Previous studies have mostly revealed the structures of inactive conformations of solubilized dopamine receptors isolated from plasma membranes. Yin et al. used cryo-electron microscopy (cryo-EM) to solve the structure of an agonist-bound form of human D2R in complex with Gi embedded in a phospholipid bilayer. Comparison of this structure with those of inactive conformations showed the agonist-induced conformational changes in transmembrane domains of D2R that could facilitate interactions with and activation of bound Gi. In addition, this study revealed interactions between distinct residues in the Gβ and Gγ subunits of the Gi protein and polar head groups in the phospholipid bilayer. Solving the structure of an active conformation of D2R in the native-like environment of the phospholipid bilayer highlights the role of the plasma membrane in regulating GPCR–G protein coupling and should help in the development of receptor-selective ligands to treat various central nervous system disorders.

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