Navarro Brugal, GemmaAguinaga Andrés, DavidAngelats Canals, EdgarMedrano Moya, MireiaMoreno Guillén, EstefaníaMallol Montero, JosefaCortés Tejedor, AntonioCanela Campos, Enric I. (Enric Isidre), 1949-Casadó, VicentMcCormick, Peter J.Lluís i Biset, CarmeFerré, Sergi2018-03-022018-03-022016-04-250021-9258https://hdl.handle.net/2445/120405The truncated non-signaling ghrelin receptor GHS-R1b has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o-coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling, from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling, but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors promoting profound qualitative changes in ghrelin-induced signaling.15 p.application/pdfeng(c) American Society for Biochemistry and Molecular Biology, 2016OligòmersDopaminaProteïnesReceptors cel·lularsOligomersDopamineProteinsCell receptorsinfo:eu-repo/semantics/article6623752018-03-02info:eu-repo/semantics/openAccess27129257