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GHSR-D2R Heteromerization Modulates Dopamine Signaling Through an Effect on G Protein Conformation

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GHSR-D2R Heteromerization Modulates Dopamine Signaling Through an Effect on G Protein Conformation GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation Marjorie Damiana, Véronique Ponsb, Pedro Renaulta, Céline M’Kadmia, Bartholomé Delorta, Lucie Hartmannc, Ali I. Kayad, Maxime Loueta, Didier Gagnea, Khoubaib Ben Haj Salaha, Séverine Denoyellea, Gilles Ferrye, Jean A. Boutine, Renaud Wagnerc, Jean-Alain Fehrentza, Jean Martineza, Jacky Mariea, Nicolas Floqueta, Céline Galèsb, Sophie Marya, Heidi E. Hammd, and Jean-Louis Banèresa,1 aInstitut des Biomolécules Max Mousseron, CNRS, Ecole Nationale Superieure de Chimie de Montepellier, Université Montpellier, 34093 Montpellier, France; bI2MC, INSERM U1048, Université de Toulouse, F-31432 Toulouse, France; cIntegral Membrane Proteins Research and Services (IMPReSs), UMR 7242 CNRS, Ecole Superieure de Biotechnologie de Strasbourg, Université de Strasbourg, F-67412 Illkirch, France; dDepartment of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600; and ePole d’expertise Biotechnologie, Chimie, Biologie, Institut de Recherches Servier, F-78290 Croissy- sur-Seine, France Edited by Robert J. Lefkowitz, Howard Hughes Medical Institute and Duke University Medical Center, Durham, NC, and approved February 21, 2018 (received for review July 22, 2017) The growth hormone secretagogue receptor (GHSR) and dopa- the purified ghrelin and dopamine receptors into lipid vesicles. By mine receptor (D2R) have been shown to oligomerize in hypotha- doing so, we demonstrate that, in liposomes, these two receptors lamic neurons with a significant effect on dopamine signaling, but interact to form a tetrameric complex comprising two each of the molecular processes underlying this effect are still obscure. We GHSR and D2R. We further bring evidence that, in this model used here the purified GHSR and D2R to establish that these two system, heteromerization alters dopamine-dependent Gi activation α receptors assemble in a lipid environment as a tetrameric complex by modulating the conformational features of the G i1 subunit. composed of two each of the receptors. This complex further recruits G proteins to give rise to an assembly with only two G protein trimers Results bound to a receptor tetramer. We further demonstrate that receptor Hetero-Oligomeric Arrangement of the Ghrelin and Dopamine heteromerization directly impacts on dopamine-mediated Gi protein Receptors in Lipid Vesicles. We first investigated the propensity of activation by modulating the conformation of its α-subunit. Indeed, GHSR to oligomerize when inserted in 200-nm PC/PE/PS/cho- PHARMACOLOGY association to the purified GHSR:D2R heteromer triggers a different lesterol large unilamellar vesicles. Large unilamellar vesicles were active conformation of Gαi that is linked to a higher rate of GTP selected to limit segregation effects associated with membrane binding and a faster dissociation from the heteromeric receptor. This curvature (10). Receptor oligomerization was investigated using is an additional mechanism to expand the repertoire of GPCR signal- three-color FRET where fluorescein (Fluo), Cy3, and Cy5 were ing modulation that could have implications for the control of dopa- used as the donor, the transmitter, and the acceptor (11). To this mine signaling in normal and physiopathological conditions. end, isolated GHSR was labeled with either of the fluorophores on a unique reactive cysteine in the extracellular part of TM7 304 GPCR | G protein | heteromer | conformational dynamics | signaling (C ) (12), mixed in equimolar amounts, and inserted into the liposomes. After proteoliposome assembly, a significant signal was observed at the emission wavelength of both Cy3 and Cy5 upon protein-coupled receptors (GPCRs) are membrane proteins involved in regulating virtually every aspect of physiology. G Significance Most membrane receptors assemble as oligomeric complexes to fulfill their function (1). GPCRs do not escape the rule, as homo- and hetero-oligomers have been described for many different G protein-coupled receptors (GPCRs) are one of the largest cell receptors (2). Although monomers can activate G proteins and surface receptor family that transmit their signal through recruit arrestins (3–5), association of different GPCRs within the coupling to intracellular partners, such as G proteins. Receptor oligomerization has been shown to be pivotal in this signaling same assembly can give rise to complexes with distinct and process. To address how oligomerization can impact on sig- unique properties (6). This heteromer-directed signaling process naling in a major physiological process, dopamine signaling, has been proposed to be pivotal in modulating some of the we used a purified GPCR heteromer composed of the ghrelin physiological function of GPCRs as well as in disease-associated and dopamine receptors to which we applied a variety of state- deregulations of signaling (6). of-the-art biochemical and biophysical approaches. By doing Ghrelin is a peptide hormone that has emerged as a major so, we provide a direct experimental evidence for a mechanism gut–brain signal controlling, among others, growth hormone se- where receptor heteromerization affects the conformation of cretion, food intake, and reward-seeking behaviors (7). These the associated G protein. This sheds light on the way a GPCR effects result from its interaction with the growth hormone se- oligomer can affect G protein activation to modulate signaling. cretagogue receptor (GHSR), a typical peptide-activated class A GPCR (7). Multiple data indicate that GHSR dimerizes with a Author contributions: M.D., V.P., P.R., J. Marie, N.F., C.G., and J.-L.B. designed research; wide array of GPCRs and that heteromerization could have an M.D., V.P., P.R., C.M., B.D., L.H., A.I.K., M.L., D.G., R.W., N.F., and C.G. performed research; impact on its signaling properties and on those of the associated K.B.H.S., S.D., G.F., J.A.B., and J.-A.F. contributed new reagents/analytic tools; M.D., V.P., receptors (8). In this context, dimerization of GHSR with the A.I.K., D.G., J.A.B., R.W., J.-A.F., J. Martinez, J. Marie, N.F., C.G., S.M., H.E.H., and J.-L.B. dopamine D2 receptor is of particular interest. Indeed, assembly analyzed data; and A.I.K., J.A.B., R.W., J.-A.F., J. Martinez, J. Marie, N.F., S.M., H.E.H., and J.-L.B. wrote the paper. of D2R with apo-GHSR, which has been demonstrated in het- erologous systems and hypothalamic neuron cultures, modulates The authors declare no conflict of interest. dopamine-dependent signaling through the βγ subunits of D2R- This article is a PNAS Direct Submission. associated Gi (9). However, so far, the molecular processes re- Published under the PNAS license. sponsible for the impact of GHSR on D2R pharmacology remain 1To whom correspondence should be addressed. Email: [email protected]. to be illuminated. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. To disentangle the mechanism through which interaction of apo- 1073/pnas.1712725115/-/DCSupplemental. GHSR with D2R could affect dopamine signaling, we assembled www.pnas.org/cgi/doi/10.1073/pnas.1712725115 PNAS Latest Articles | 1of6 Fluo excitation (Fig. 1A). This points to an oligomeric assembly Cy5 at a 10-fold GPCR-to-GHSR molar ratio and assembled into comprising at least three GHSR protomers. liposomes. A significantly lower FRET signal was observed in the We then assembled into the liposomes labeled GHSR with un- presence of D1R and D2R only (Fig. 1B). In both cases, whereas a labeled potential partners and monitored through Fluo-Cy3 (two- two-color FRET signal persisted, no more detectable three-color color) and Fluo-Cy3-Cy5 (three-color) FRET whether the additional FRET could be observed. Of importance, most of the D2R and of receptor competed with GHSR homo-oligomerization. Because the negative control receptors (BLT1, MT1R) inserted into the GHSR is essentially monomeric before insertion into the liposomes lipid vesicle in the same inside-in orientation as GHSR (SI Ap- (SI Appendix,Fig.S1), the assay reports on the propensity of isolated pendix, Fig. S2). A saturation-like profile was also obtained when receptors to form oligomers upon detergent-to-lipid exchange. To the FRET signal was measured at increasing D2R-to-GHSR C validate the method, Fluo-, Cy3-, and Cy5-labeled GHSRs were first molar ratios (Fig. 1 ). The ratio at which half of the change in mixed with a 10-fold molar excess of unlabeled GHSR before as- the signal occurred was similar for two- and three-color FRET, sembly into liposomes. Under such conditions, a decrease of both suggesting that both changes result from the same molecular two-color and three-color FRET signals was observed (Fig. 1B), event. Overall, these data indicate that D2R disrupts GHSR oligo- indicating that the unlabeled receptor competed with the assembly mers while maintaining some homodimeric interactions. GHSR:D2R of labeled-GHSR oligomers. Consistently, saturation-like plots were proximity in the lipid vesicles was further confirmed by measuring obtained when varying the molar ratio of unlabeled-to-labeled FRET between GHSR labeled with a Tb-cryptate donor on Cys304 and D2R labeled with an XL255-labeled antibody reacting GHSR (Fig. 1C), with a percent of fluorescence change at a with its N-terminal Flag-tag (Fig. 1D). 1:1 molar ratio in the same range than that measured in a cellular system (9). We then investigated whether other purified GPCRs The GHSR:D2R Heteromer. We then purified the GHSR:D2R com- could compete with GHSR oligomer formation. These included two plex from the proteoliposomes. To this end, lipid vesicles con- receptors that had been shown to dimerize with GHSR (D1R, D2R) taining GHSR and D2R were solubilized with the styrene maleic and unrelated GPCRs [BLT1, BLT2, MT1R, 5-HT4(a)]. Either of acid (SMA) copolymer (13, 14) to get membrane discs (SMALPs) these receptors was mixed with GHSR labeled with Fluo, Cy3, and encapsulating the receptors.
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