Dopamine directly modulates GABAA receptors

Dopamine is a critical neuromodulator that activates GPCRs in mammals or ligand-gated ion channels in invertebrates. The present study demonstrates that dopamine (0.1-10 mm) exerts novel, opposing effects on different populations of mammalian (rat) GABAA receptors. Using whole-cell patch-clamp electrophysiology, we observed direct dopamine-mediated inhibition of tonic-level (1 μm) GABA-evoked currents in untransfected striatal neurons that could be recapitulated in HEK293 cells containing α1β3 or α1β2γ2 subunits. Surprisingly, direct activation by dopamine was seen in the absence of GABA with α1β2γ2, α5β3γ2, or α1β3γ2 transfections. This activity was also present in α1β3γ2 receptors containing a mutant β3 subunit (H267A [(Z)β3]) insensitive to trace levels of inhibitory Zn(2+). Dopamine activation required β and γ subunits but not α subunits ((Z)β3γ2 EC50 value, 660 μm). Dopamine activity was fully blocked by picrotoxin but not GABAA competitive antagonists, and was strongly correlated with spontaneous receptor activity. We also report opposing effects of bicuculline and gabazine, such that bicuculline surprisingly activated non-α-containing (β3γ2) GABAA receptors, whereas gabazine suppressed spontaneous activity in these receptors. Our results suggest that dopamine may directly inhibit GABAA receptors that are both immediately adjacent to dopamine release sites in the striatum and activated by tonic GABA. Furthermore, synaptic/phasic release of dopamine may directly enhance signaling at some spontaneously active noncanonical GABAA receptors that lack α subunits.