Over the last few years, several studies have provided generated for the existence of a macromolecular signaling complex on the plasma membrane. This complex is postulated to contain G proteins, GPCRs, GIRK channels and regulatory proteins92-97 (see review by ref2) (Figure 2C). First, because GIRK channels remain open as long as Gβγ subunits are available, Gα subunits are expected to remain near the channel to terminate GIRK channel activation, through formation of the inactive Gαβγ heterotrimer (Box 1). Second, PTX-sensitive Gα subunits can associate directly with GIRK channels and alter channel gating84,85,98,99. In fact, Gα may also be involved in establishing receptor specificity such that stimulation of GPCRs that couple to only PTX-sensitive G proteins activate GIRK channels84,100. Third, spectroscopic studies with fluorescently tagged GPCRs, G proteins and regulator of G protein signaling (RGS) proteins, have provided details on the spatial relationship between proteins within this macromolecular signaling complex26,92,94,96,101,102 (see Box 2). Interestingly, spectroscopic studies with Gαiβγ heterotrimers have suggested that G protein activation involves a conformational rearrangement of the Gαi and Gβγ subunits, in contrast to the canonical model
