Co-activation of GPCRs facilitate GIRK-dependent current.

The activity of dopamine neurons is dependent on both intrinsic properties and afferent projections. One potent form of inhibition is mediated by the activation of two inhibitory G protein-coupled receptors, D2 and GABA receptors. Each of these receptors activates G protein-coupled inwardly rectifying potassium (GIRK) channels. Recordings in brain slices have shown that co-activation using saturating concentrations of agonists results in occlusion of the GIRK current. The present study examined the interaction between D2 and GABA receptors using transient applications of sub-saturating concentrations of agonists where the co-application of one agonist resulted in both facilitation and inhibition (desensitization) of the other. The heterologous facilitation was modelled based on the known cooperative interaction between the G protein βγ subunits and GIRK channels. The results indicate that a low tonic level of G βγ results in facilitation of GIRK current and a high level of G βγ results in occlusion. The kinetics of the current induced by transient receptor activation is prolonged in each case. The results suggest that the cooperative interaction between G βγ subunits and GIRK channels determines both the amplitude and kinetics of GPCR-dependent current. KEY POINTS: Inhibitory D2 and GABA receptors modulate dopamine neuron activity through shared G protein-coupled inwardly rectifying potassium (GIRK) channels. This study reports robust bidirectional interactions between these two converging receptor pathways. Coincident activation of D2 and GABA receptors leads to facilitation of GIRK channel currents, augmenting both amplitude and prolonging the duration of phasic responses. Activation of either D2 or GABA receptors also acutely desensitized the GIRK channel current induced by D2 receptor activation that rapidly recovers following termination of desensitizing stimulus. Results demonstrate that the activity of either G protein-coupled receptor system must be considered in the context of other G protein-coupled receptors.