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

Functional interactions between the G protein-coupled dopamine D-1 and histamine H-3 receptors have been described in the brain. In the present study we investigated the existence of D-1-H-3 receptor heteromers and their biochemical characteristics. D-1-H-3 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 D-1 or H-3 receptors. Bioluminescence Resonance Energy Transfer and binding assays confirmed that D-1 and H-3 receptors can heteromerize. Activation of histamine H-3 receptors did not lead to signalling towards the MAPK pathway unless dopamine D-1 receptors were co-expressed. Also, dopamine D-1 receptors, usually coupled to G(s) proteins and leading to increases in cAMP, did not couple to G(s) but to G(i) 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. D-1-H-3 receptor heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a G(s)-independent and G(i)-dependent manner. An antagonist of one of the receptor units in the D-1-H-3 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.