Dopamine D1 and corticotrophin‐releasing hormone type‐2α receptors assemble into functionally interacting complexes in living cells

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Abstract
Background and Purpose: Dopamine and corticotrophin‐releasing hormone (CRH; also known as corticotrophin‐releasing factor) are key neurotransmitters in the interaction between stress and addiction. Repeated treatment with cocaine potentiates glutamatergic transmission in the rat basolateral amygdala/cortex pathway through a synergistic action of D1‐like dopamine receptors and CRH type‐2α receptors (CRF2α receptors). We hypothesized that this observed synergism could be instrumented by heteromers containing the dopamine D1 receptor and CRF2α receptor.Experimental Approach: D1/CRF2α receptor heteromerization was demonstrated in HEK293T cells using co‐immunoprecipitation, BRET and FRET assays, and by using the heteromer mobilization strategy. The ability of D1 receptors to signal through calcium, when singly expressed or co‐expressed with CRF2α receptors, was evaluated by the calcium mobilization assay.Key Results: D1/CRF2α receptor heteromers were observed in HEK293T cells. When singly expressed, D1 receptors were mostly located at the cell surface whereas CRF2α receptors accumulated intracellularly. Interestingly, co‐expression of both receptors promoted D1 receptor intracellular and CRF2α receptor cell surface targeting. The heteromerization of D1/CRF2α receptors maintained the signalling through cAMP of both receptors but switched D1 receptor signalling properties, as the heteromeric D1 receptor was able to mobilize intracellular calcium upon stimulation with a D1 receptor agonist.Conclusions and Implications: D1 and CRF2α receptors are capable of heterodimerization in living cells. D1/CRF2α receptor heteromerization might account, at least in part, for the complex physiological interactions established between dopamine and CRH in normal and pathological conditions such as addiction, representing a new potential pharmacological target.
Funding Information
  • FONDECYT (1070340, 1110392, 7070246, 7080124 anf 1130079)
  • Millenium Science Initiative (MSI) (P06/008-F and P10/063-F)
  • MINECO and ICREA Academia-2010 from Catalan Institution for Research and Advanced Studies (ICREA) (SAF2011-24779 and CSD2008-00005)

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