Differential effect of amphetamine over the corticotropin-releasing factor CRF2 receptor, the orexin OX1 receptor and the CRF2-OX1 heteroreceptor complex

NEUROPHARMACOLOGY

卷:152

Article

Navarro, Gemma^1,2  Medrano, Mireia^2,3  Aguinaga, David^2,3  Vega-Quiroga, Ignacio⁴  Lillo, Alejandro³  Jimenez, Jasmina²  Casanovas, Mireia^2,3  Canela, Enric I.^2,3  Mallol, Josefa^2,3  Gysling, Katia⁴  Franco, Rafael^2,3 

[1] Univ Barcelona, Dept Biochem & Physiol, Pharm & Food Sci Sch, Barcelona, Spain

[2] Inst Salud Carlos III, Ctr Invest Red Enfermedades Neurodegenerat CIBERN, Madrid, Spain

[3] Univ Barcelona, Dept Biochem & Mol Biomed, Mol Neurobiol Lab, Barcelona, Spain

[4] Pontificia Univ Catolica Chile, Fac Biol Sci, Dept Cellular & Mol Biol, Santiago, Chile

关键词: Heteromers;    G-protein-coupled receptor;    GPCR;    GPCR heteromer;    Stress;    Addiction;    Orexin;    Sigma receptors;   

DOI  :  10.1016/j.neuropharm.2018.11.014

来源: Elsevier

【 摘 要 】

Stress is one of the factors underlying drug seeking behavior that often goes in parallel with loss of appetite. We here demonstrate that orexin 1 receptors (OX1R) may form complexes with the corticotropin releasing factor CRF2 receptor. Two specific features of the heteromer were a cross-antagonism and a blockade by CRF2 of OX1R signaling. In cells expressing one of the receptors, agonist-mediated signal transduction mechanisms were potentiated by amphetamine. Sigma 1 (sigma(1)) and 2 (sigma(2)) receptors are targets of drugs of abuse and, despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is not known. We here show that sigma(1) receptors interact with CRF2 receptors and that sigma(2) receptors interact with OX1R. Moreover, we show that amphetamine effect on CRF2 receptors was mediated by sigma R-1 whereas the effect on OX1 receptors was mediated by sigma R-2. Amphetamine did potentiate the negative cross-talk occurring within the CRF2-OX1 receptor heteromer context, likely by a macromolecular complex involving the two sigma receptors and the two GPCRs. Finally, in vivo microdialysis experiments showed that amphetamine potentiated orexin A-induced dopamine and glutamate release in the ventral tegmental area (VTA). Remarkably, the in vivo orexin A effects were blocked by a selective CRF2R antagonist. These results show that amphetamine impacts on the OX1R-, CRF2R- and OX1R/CRF2R-mediated signaling and that cross-antagonism is instrumental for in vivo detection of GPCR heteromers. This article is part of the Special Issue entitled 'Receptor heteromers and their allosteric receptor-receptor interactions'.

【 授权许可】

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