Synergistic activation of G protein-gated inwardly rectifying potassium channels by the βγ subunits of G proteins and Na+ and Mg2+ ions

Native and recombinant G protein-gated inwardly rectifying potassium (GIRK) channels are directly activated by the beta gamma subunits of GTP-binding (G) proteins. The presence of phosphatidylinositol-bis-phosphate (PIP2) is required for G protein activation. Formation (via hydrolysis of ATP) of endogenous PIP2 or application of exogenous PIP2 increases the mean open time of GIRK channels and sensitizes them to gating by internal Na+ ions. In the present study, we show that the activity of ATP- or PIP2-modified channels could also be stimulated by intracellular Mg2+ ions. In addition, Mg2+ ions reduced the single-channel conductance of GIRK channels, independently of their gating ability. Both Na+ and Mg2+ ions exert their gating effects independently of each other or of the activation by the G(beta gamma) subunits. At high levels of PIP2, synergistic interactions among Na+, Mg2+, and G(beta gamma) subunits resulted in severalfold stimulated levers of channel activity. Changes in ionic concentrations and/or G protein subunits in the local environment of these K+ channels could provide a rapid amplification mechanism for generation of graded activity, thereby adjusting the level of excitability of the cells.