Voltage-Dependent Dopamine Potency at D(1)-Like Dopamine Receptors

In recent years, transmembrane voltage has been found to modify agonist potencies at several G protein-coupled receptors (GPCRs). Whereas the voltage sensitivities of the Gα(i/o)-coupled dopamine D(2)-like receptors (D(2)R, D(3)R, D(4)R) have previously been investigated, the putative impact of transmembrane voltage on agonist potency at the mainly Gα(s/olf)-coupled dopamine D(1)-like receptors (D(1)R, D(5)R) has hitherto not been reported. Here, we assayed the potency of dopamine in activating G protein-coupled inward rectifier potassium (GIRK) channels co-expressed with D(1)R and D(5)R in Xenopus oocytes, at -80 mV and at 0 mV. Furthermore, GIRK response deactivation rates upon dopamine washout were measured to estimate dopamine dissociation rate (k(off)) constants. Depolarization from -80 to 0 mV was found to reduce dopamine potency by about 7-fold at both D(1)R and D(5)R. This potency reduction was accompanied by an increase in estimated dopamine k(off)s at both receptors. While the GIRK response elicited via D(1)R was insensitive to pertussis toxin (PTX), the response evoked via D(5)R was reduced by 64% (-80 mV) and 71% (0 mV) in the presence of PTX. Injection of oocytes with Gα(s) antisense oligonucleotide inhibited the D(1)R-mediated response by 62% (-80 mV) and 76% (0 mV) and abolished the D(5)R response when combined with PTX. Our results suggest that depolarization decreases dopamine affinity at D(1)R and D(5)R. The voltage-dependent affinities of dopamine at D(1)R and D(5)R may be relevant to the functions of these receptors in learning and memory.