Delineation of the conserved functional properties of D 1A , D 1B and D 1C dopamine receptor subtypes in vertebrates

Summry— The three main subtypes of dopamine D 1 receptor (D 1A , D 1B and D 1C ) subtypes found in most vertebrate groups were generated by two major steps of gene duplications, early in evolution. To identify the functional characteristics contributing to conservation of these paralogous D 1 receptors in vertebrates, the pharmacological and functional properties of fish ( Anguilla anguilla ), amphibian ( Xenopus lævis ) and human receptors were systematically analysed in transfected cells. The ligand‐binding parameters appeared essentially similar for orthologous receptors, but differed significantly among the subtypes. The D 1A receptors from the three species displayed low intrinsic activity and a fast rate of agonist‐induced desensitization. All the orthologous D 1B receptors exhibited a similar desensitization time‐course, but with smaller amplitude of decrease than D 1A receptors, in agreement with their higher basal activity. In contrast, D 1C receptors, which do not exist in mammals, have low intrinsic activity and exhibit only weak, but rapid, agonist‐induced desensitization, without any changes upon longer treatment with agonist. Thus, each of the three D 1 receptor subtypes are characterized by activation and desensitization properties, in a sequence‐specific manner, which has been probably acquired early after gene duplications, and constrained their conservation during vertebrate evolution. These properties have been instrumental to adapt dopamine system to the physiology of the numerous neuronal networks and functions they control in the large and complex brains of vertebrates.