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G protein gated inward rectifier K +  (GIRK) channels open and thereby silence cellular electrical activity when inhibitory G protein coupled receptors (GPCRs) are stimulated. Here we describe an assay to measure neuronal GIRK2 activity as a function of membrane-anchored G protein concentration. Using this assay we show that four Gβγ subunits bind cooperatively to open GIRK2, and that intracellular Na +  – which enters neurons during action potentials – further amplifies opening mostly by increasing Gβγ affinity. A Na +  amplification function is characterized and used to estimate the concentration of Gβγ subunits that appear in the membrane of mouse dopamine neurons when GABA B  receptors are stimulated. We conclude that GIRK2, through its dual responsiveness to Gβγ and Na + , mediates a form of neuronal inhibition that is amplifiable in the setting of excess electrical activity.

Cooperative regulation by G proteins and Na + of neuronal GIRK2 K + channels