Dopamine Directly Modulates GABAA Receptors

Dopamine is a critical neuromodulator that activatesGPCRsinmammalsor ligand-gated ion channels in invertebrates. The present study demonstrates that dopamine (0.1-10mM) 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 mu M) GABA-evoked currents in untransfected striatal neurons that could be recapitulated in HEK293 cells containing alpha 1 beta or alpha 1 beta 2 gamma 2 subunits. Surprisingly, direct activation by dopamine was seen in the absence of GABA with alpha 1 beta 2 gamma 2, alpha 5 beta 3 gamma 2, or alpha 1 beta 3 gamma 2 transfections. This activity was also present in alpha 1 beta 3 gamma 2 receptors containing a mutant beta 3 subunit (H267A [ (Z)beta 3]) insensitive to trace levels of inhibitory Zn2+. Dopamine activation required beta and gamma subunits but not alpha subunits ((Z)beta 3 gamma 2 EC50 value, 660 mu M). Dopamine activity was fully blocked by picrotoxin but not GABA(A) competitive antagonists, and was strongly correlated with spontaneous receptor activity. Wealso report opposing effects of bicuculline and gabazine, such that bicuculline surprisingly activated non-alpha-containing (beta 3 gamma 2) GABA(A) receptors, whereas gabazine suppressed spontaneous activity in these receptors. Our results suggest that dopamine may directly inhibit GABA(A) 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 GABA(A) receptors that lack alpha subunits.