Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors

Background and purpose: Functional interactions between the G protein‐coupled dopamine D1 and histamine H3 receptors have been described in the brain. In the present study we investigated the existence of D1–H3 receptor heteromers and their biochemical characteristics. Experimental approach: D1–H3 receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen‐activated protein kinase (MAPK) and adenylyl cyclase pathways was studied in co‐transfected cells and compared with cells transfected with either D1 or H3 receptors. Key results: Bioluminescence Resonance Energy Transfer and binding assays confirmed that D1 and H3 receptors can heteromerize. Activation of histamine H3 receptors did not lead to signalling towards the MAPK pathway unless dopamine D1 receptors were co‐expressed. Also, dopamine D1 receptors, usually coupled to Gs proteins and leading to increases in cAMP, did not couple to Gs but to Gi in co‐transfected cells. Furthermore, signalling via each receptor was blocked not only by a selective antagonist but also by an antagonist of the partner receptor. Conclusions and implications: D1–H3 receptor heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a Gs‐independent and Gi‐dependent manner. An antagonist of one of the receptor units in the D1–H3 receptor heteromer can induce conformational changes in the other receptor unit and block specific signals originating in the heteromer. This gives rise to unsuspected therapeutic potentials for G protein‐coupled receptor antagonists.