Significant role of the truncated Ghrelin Receptor GHS-1Rb in Ghrelin-induced signaling in neurons

Gemma Navarro, David Aguinaga, Edgar Angelats, Mireia Medrano, Estefania Moreno, Josefa Mallol, Antonio Cortes, Enric I Canela, Vicent Casado, Peter J McCormick, Carme Lluis, Sergi Ferre

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Abstract

The 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.
Original languageEnglish
Pages (from-to)13048-13062
Number of pages15
JournalJournal of Biological Chemistry
Volume291
Early online date25 Apr 2016
DOIs
Publication statusPublished - 17 Jun 2016

Keywords

  • cAMP
  • dopamine receptor
  • neuron
  • oligomerization
  • trafficking
  • HEK-293T cells
  • ghrelin
  • ghrelin receptor

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