Critical Determinants of the G Protein γ Subunits in the Gβγ Stimulation of G Protein-activated Inwardly Rectifying Potassium (GIRK) Channel Activity

Abstract

The ␤␥ subunits of G proteins modulate inwardly rectifying potassium (GIRK) channels through direct interactions. Although GIRK currents are stimulated by mammalian G␤␥ subunits, we show that they were inhibited by the yeast G␤␥ (Ste4/Ste18) subunits. A chimera between the yeast and the mammalian G␤ 1 subunits (ym␤) stimulated or inhibited GIRK currents, depending on whether it was co-expressed with mammalian or yeast G␥ subunits, respectively. This result underscores the critical functional influence of the G␥ subunits on the effectiveness of the G␤␥ complex. A series of chimeras between G␥ 2 and the yeast G␥ revealed that the C-terminal half of the G␥ 2 subunit is required for channel activation by the G␤␥ complex. Point mutations of G␥ 2 to the corresponding yeast G␥ residues identified several amino acids that reduced significantly the ability of G␤␥ to stimulate channel activity, an effect that was not due to improper association with G␤. Most of the identified critical G␥ residues clustered together, forming an intricate network of interactions with the G␤ subunit, defining an interaction surface of the G␤␥ complex with GIRK channels. These results show for the first time a functional role for G␥ in the effector role of G␤␥.

Interaction of the Ca2+-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function

“…Stimulated GPCRs activate G␣␤␥ heterotrimers to release G␤␥ subunits that can interact directly with Kir3 channels (designated as GIRK) to activate them, but this mechanism has not been shown to apply to other Kir channels (1,5,15,27,32,34). The role of G␣ subunits in the regulation of GIRK signaling has been controversial for a number of years (12).…”

Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior

“…However, we have not proven that AGS3͞␤␥ regulation of PKA signaling, which we show in NAc͞striatal neurons in vitro, is responsible in the NAc for AGS3͞␤␥ regulation of heroin-seeking behavior in vivo. Other actions of ␤␥ subunits, such as activation of G proteinactivated inwardly rectifying potassium channels, could also be involved (35).…”

Melatonin: A hormone that modulates pain

“…The Gβγ subunit complex then functions as a dimmer that activates various effectors including enzymes and ion channels (Neves et al 2002). Two mechanisms have been proposed whereby G-protein coupled receptor activation can modify ion channel function: (1) an indirect ion channel phosphorylation through protein kinases; and (2) a direct Gβγ binding the ion channels (Dolphin 2003;Peng et al 2003).…”