Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes

CAROLINA WEDEMEYER; JUAN D. GOUTMAN; MARIA E. AVALE; LUCIA F. FRANCHINI; MARCELO RUBINSTEIN; DANIEL J. CALVO

EUROPEAN JOURNAL OF PHARMACOLOGY

Año: 2007 vol. 562 p. 165 - 173

0014-2999

Dopamine D4 receptors (D4Rs) are largely expressed in the prefrontal cortex. This localization suggests a key role for D4Rs in mediating the dopaminergic control of multiple cognitive functions. In this study we demonstrate functional activation of different human D4R polymorphic variants by noradrenaline (NA) and serotonin (5-HT) besides dopamine (DA). Human D4.2, D4.4 and D4.7 receptors were individually co-expressed with G protein–regulated inwardly rectifying potassium channels (GIRK) in Xenopus oocytes. D4R functionally couples to GIRK1 through oocyte´s Gi/o proteins modulating channel gating. GIRK1 currents were evoked by hyperpolarization and recorded by two-electrode voltage-clamp. D4.2, D4.4 and D4.7 receptors similarly modulated GIRK1 currents, stimulation of these hD4R variants by DA, NA and 5-HT increased GIRK1 currents amplitude. Monoamines actions on the D4R variants were blocked by both the selective D2-like antagonist sulpiride and the specific D4R antagonist PNU101387. Dose-response analysis showed that DA was significantly more potent on D4.2 and D4.7 receptors (both EC50´s = 1 nM) than on D4.4 receptors (EC50 = 5 nM) and that NA, or 5-HT, induced equivalent actions on D4.2, D4.4 or D4.7 receptors. NA, like DA, is a full agonist with EC50´s @ 50 nM, while 5-HT is a partial agonist with EC50´s @ 1.5 µM. Our data indicate that D4Rs can be stimulated by any of the three major monoaminergic neurotransmitters that modulate prefrontal cortical neural networks. These results also suggest that D4Rs can be differentially activated by DA, but not by NA or 5-HT. Thus, DA actions on human D4Rs might vary among individuals, fundamentally depending on which allele is eventually expressed. The nature and specificity of this presumed monoamine crosstalk at the D4Rs and its possible relevancy for the control of neural mechanisms underlying prefrontal cortical function is discussed.