Pharmacology of a human dopamine D4 receptor expressed in HEK293 cells

Dopamine receptors play an important role in neurotransmission within the central nervous system, as evidenced by their affinity to and apparent site of action of a variety of psychotropic agents. The cloning of dopamine receptor subtypes makes possible the discovery of subtype-selective agonist and antagonist compounds useful for the study of receptor physiology and for the development of more effective treatments for disturbances stemming from aberrant dopamine neurotransmission. We describe in this report the receptor pharmacology of a human D4-dopamine receptor expressed in HEK293 cells from a synthetic gene. The affinities of monoaminergic antagonists in competition with [3H]spiperone-labeled sites in these cells matched very closely their rank order potency measured by other investigators for D4 receptors expressed in COS-7 cells. Further, the sites expressed in the HEK293-D4-24 line met six specific pharmacological criteria by which the D4 subtype has been distinguished from other D2-like dopamine receptors. The site expressed in this cell investigators for D4 receptors expressed in COS-7 cells. Further, the sites expressed in the HEK293-D4-24 line met six specific pharmacological criteria by which the D4 subtype has been distinguished from other D2-like dopamine receptors. The site expressed in this cell line thus bears the earmarks of a human D4-dopamine receptor. Competition of several agonists best fit a two-site binding model. This result, along with the measured 10-fold GTP-shift for dopamine, strongly suggests functional coupling of this receptor to endogenous G-proteins.(ABSTRACT TRUNCATED AT 250 WORDS)