Pharmacological and molecular basis for dopamine D-2 receptor diversity

This review will focus on the main lines of evidence that suggest the existence of multiple types of dopamine D-2 receptors. Dopamine D-2 receptors share structural elements suggesting that they belong to a gene superfamily classified as G-protein-coupled receptors and show an archetypical topology predicted to consist of seven putative transmembrane domains. Activation of D-2 receptors results in a variety of responses, including inhibition of cyclic AMP formation, inhibition of phosphoinositol turnover, increase of K-channel activity, and inhibition of Ca influx. The G protein(s) linking the D-2 receptors to these responses have not been completely identified, nor has the possible hierarchy of these regulatory proteins in transforming the incoming signal into a change of second-messenger levels. A lot of experimental data support the hypothesis that there are multiple signal-processing pathways activated by dopamine through D-2-receptor stimulation. Recently, the identification of dopaminergic drugs that discriminate among the different transduction pathways and the isolation of distinct cDNAs encoding proteins that share binding profile indicative of D-2 receptors clearly indicate multiple forms of D-2 receptors. Pharmacologically, at least two distinct categories of dopamine D-2 receptors exist in rat pituitary. The first (D-2a) is insensitive to BHT 920 and coupled to inhibition of adenylyl cyclase activity; the second (D-2b) is activated by BHT 920 and linked to voltage-dependent K channels. The two types of dopamine D-2 receptors differ in their structure, G-protein-coupled and effector. Each of the three basic receptor units shows a certain degree of heterogeneity, which may affect the quality and the kinetic of the response. This variety may represent the molecular basis for the diversity in pharmacological and functional profiles of different dopamine D-2 receptors located in various brain areas and peripheral tissues.