Voltage-Dependent Dopamine Potency at D1-Like Dopamine Receptors

Abstract

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 D₂-like receptors (D₂R, D₃R, D₄R) have previously been investigated, the putative impact of transmembrane voltage on agonist potency at the mainly Gα_s/olf-coupled dopamine D₁-like receptors (D₁R, D₅R) 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 D₁R and D₅R in <i>Xenopus</i> 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 D₁R and D₅R. This potency reduction was accompanied by an increase in estimated dopamine k_offs at both receptors. While the GIRK response elicited via D₁R was insensitive to pertussis toxin (PTX), the response evoked via D₅R 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 D₁R-mediated response by 62% (-80 mV) and 76% (0 mV) and abolished the D₅R response when combined with PTX. Our results suggest that depolarization decreases dopamine affinity at D₁R and D₅R. The voltage-dependent affinities of dopamine at D₁R and D₅R may be relevant to the functions of these receptors in learning and memory.