The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

Synergistic interplay of Gβγ and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity

“…In GIRK channels, approximately 12 sites across the protein have been identified as important for Gβγ binding that combine to accommodate 4 Gβγ molecules in the functional tetramer [9, 11, 34]. Moreover, distinct high- and low-affinity sites exist in GIRKs that determine basal activation and receptor-mediated activation, respectively [11]. These aspects of molecular recognition need to be determined for Kv7.4.…”

“…Our data show that Kv7.4 activity is attenuated by Gβγ inhibitors, implying that there is a persistent influence of Gβγ maintaining channel activity. Again, there is a parallel with GIRK channels that have a basal level of activity due to constitutive binding of Gβγ [11]. The free Gβγ maintaining Kv7.4 activity may be the product of binding of Gα to the channel protein and the associated tethering of Gβγ as shown for Kir3.1 [11], localized G-protein coupled receptor activity or a labile free pool of Gβγ.…”

“…Again, there is a parallel with GIRK channels that have a basal level of activity due to constitutive binding of Gβγ [11]. The free Gβγ maintaining Kv7.4 activity may be the product of binding of Gα to the channel protein and the associated tethering of Gβγ as shown for Kir3.1 [11], localized G-protein coupled receptor activity or a labile free pool of Gβγ. Irrespective of these unknowns, we have identified that Kv7.4 activity is crucially dependent on a synergistic interplay between PIP 2 and Gβγ.…”

“…It is acknowledged that Kv7 channels have an obligatory requirement for phosphatidylinositol 4,5-bisphosphate (PIP 2 ) [4, 12, 18], but we recently described how the Kv7.4 channel, important for normal vascular function [6, 7, 15], requires G-protein βγ subunits (Gβγ) for its voltage-dependent activity [27]. Few ion channels are directly regulated by Gβγ with the best studied being the G protein coupled inwardly rectifying potassium (GIRK) channel that controls electrical excitability in neurons and cardiac cells [9–11, 19]. This channel is comprised of Kir3.1–3.4 subunits and Gβγ enhance open probability by stabilizing the interaction of PIP 2 [9, 13, 20].…”

Collision coupling in the GABAB receptor–G protein–GIRK signaling cascade

“…Note that this explanation requires Ga GTP to actively regulate GIRK's activation kinetics, as proposed in the past ( [34,35]; reviewed in ref. [53]). Another potential candidate is the Gabc heterotrimer, which is not present in saturating amount even in the Gbc-anchoring GIRK1/ 2 [39], and even more so in GIRK2.…”