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

Navarro, Gemma, Aguinaga, David, Angelats, Edgar, Medrano, Mireia, Moreno, Estefania, Mallol, Josefa, Cortes, Antonio, Canela, Enric I, Casado, Vicent, McCormick, Peter J, Lluis, Carme and Ferre, Sergi (2016) Significant role of the truncated Ghrelin Receptor GHS-1Rb in Ghrelin-induced signaling in neurons. Journal of Biological Chemistry, 291. pp. 13048-13062. ISSN 0021-9258

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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.

Item Type: Article
Uncontrolled Keywords: camp,dopamine receptor,neuron,oligomerization,trafficking,hek-293t cells,ghrelin,ghrelin receptor
Faculty \ School: Faculty of Science > School of Pharmacy
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Depositing User: Pure Connector
Date Deposited: 09 May 2016 16:00
Last Modified: 24 Jul 2019 22:16
URI: https://ueaeprints.uea.ac.uk/id/eprint/58607
DOI: 10.1074/jbc.M116.715144

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