Agonist potency at some neurotransmitter receptors has been shown to be regulated by transmembrane voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by autoreceptors and in synaptic plasticity. We have recently described the voltage-sensitivity of the dopamine D-2L, receptor and we now extend our studies to include the other members of the D-2-like receptor subfamily; the D-2S, D-3, and D-4 cloparnine receptors. Electrophysiological recordings were performed on Xenopus oocytes coexpressing human dopamine D-2S, D-3, or D-4 receptors with G protein-coupled potassium (GIRK) channels. Comparison of concentration-response relationships at -80 mV and at 0 mV for dopamine-mediated GIRK activation revealed significant rightward shifts for both D-2S and D-4 upon depolarization. In contrast, the concentration-response relationships for D-3-mediated GIRK activation were not appreciably different at the two voltages. Our findings Provide new insight into the functional differences of these closely related receptors. (C) 2008 Elsevier Inc. All rights reserved.