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Dissociation of the heterotrimeric GTP-binding protein (G protein) βγ subunits from the α subunit is a prerequisite step in the ability of these proteins to signal to downstream effectors. There is evidence that ions such as Na+ and Cl- can facilitate this dissociation. Interestingly, for KACh, the first known effector for Gβγ, intracellular Na+ can also activate the channel independently of Gβγ. Both Gβγ and Na+ strengthen channel interactions with the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), an event thought to be essential in opening the channel. PIP2 interacts with channel regions that form a binding pocket proximal to the transmembrane domains and is likely to exert a tangential, pulling force to mechanically open a gate at the cytoplasmic face of the channel pore. The tangential force generated by channel-PIP2 interactions is the likely force behind gating in all inwardly rectifying K+ channels. The gate opens when the lower part of the pore-lining transmembrane α helix pivots around a glycine residue in the middle of the helix. This mechanism of channel gating is conserved among K+ channels from bacteria to mammals and may represent a common mechanism for K+ channel gating.