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Title: Significant Role of the Truncated Ghrelin Receptor GHS-1Rb in Ghrelin-Induced Signaling in Neurons
Author: Navarro Brugal, Gemma
Aguinaga Andrés, David
Angelats, Edgar
Medrano, Mireia
Moreno Guillén, Estefanía
Mallol Montero, Josefa
Cortés Tejedor, Antonio
Canela Campos, Enric I.
Casadó, Vicent
McCormick, Peter J.
Lluís i Biset, Carme
Ferré, Sergi
Keywords: Oligòmers
Receptors cel·lulars
Cell receptors
Issue Date: 25-Apr-2016
Publisher: American Society for Biochemistry and Molecular Biology
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.
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It is part of: Journal of Biological Chemistry, 2016, vol. 291, p. 13048-13062
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ISSN: 0021-9258
Appears in Collections:Articles publicats en revistes (Bioquímica i Fisiologia)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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