Marked changes in signal transduction upon heteromerization of dopamine D 1 and histamine H 3 receptors

Abstract

Background and purpose: 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. Experimental approach: 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. Key results: 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. Conclusions and Implications: 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 antaaonists. © 2009 The British Pharmacological Society All rights reserved.