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Original Article

Synergistic Activation of G Protein–Gated Inwardly Rectifying Potassium Channels by the β Subunits of G Proteins and Na⁺ and Mg²⁺ Ions

^a From the Department of Physiology and Biophysics, Mount Sinai School of Medicine of the New York University, New York, New York 10029
Department of Physiology and Biophysics, Mount Sinai School of Medicine of the New York University, New York, NY 10029.Fax: 212-860-3369;

logothetis{at}msvax.mssm.edu

Native and recombinant G protein–gated inwardly rectifying potassium (GIRK) channels are directly activated by the β 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_β subunits. At high levels of PIP₂, synergistic interactions among Na⁺, Mg²⁺, and G_β subunits resulted in severalfold stimulated levels 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.

Key Words: G protein–gated inwardly rectifying potassium channels • phosphatidylinositol-bis-phosphate • G_β gating • Mg²⁺ gating • Na⁺ gating

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