EPINEPHRINE AND NOREPINEPHRINE ACT AS POTENT AGONISTS AT THE RECOMBINANT HUMAN DOPAMINE D4 RECEPTOR

The catecholamines dopamine (DA), epinephrine (EP), and norepinephrine (NE) play important roles in learning and memory, emotional states, a nd control of voluntary movement, as well as cardiovascular and kidney function. They activate distinct but overlapping neuronal pathways th rough five distinct DA receptors (D1R-D5R) and at least 10 different a drenergic receptors (alpha 1a/b/c, alpha 2a/b/c-1/c-2, and beta 1/beta 2/beta 3). The D4R, which is localized to mesolimbic areas of the bra in implicated in affective and emotional behavior, has a deduced amino acid sequence with homology to both adrenergic and dopaminergic recep tor subtypes. We report here that DA, EP, and NE all show binding in t he nanomolar range to three isoforms of the recombinant human D4R (hD4 R): D4.2, D4.4, and D4.7. Submicromolar concentrations of DA, EP, and NE were sufficient to activate hD4R isoforms in two different function al assays: agonist-induced guanosine 5'-O-(3-[S-35]thiotriphosphate) b inding and modulation of adenylyl cyclase activity. DA was approximate ly fivefold more potent than EP and NE at the D4R, whereas activation of the human D2R required at least 100-fold higher catecholamine conce ntrations. Functional activation of the D4R by multiple neurotransmitt ers may provide a novel mechanism for integration of catecholamine sig naling in the brain and periphery.