Differential Control of Potassium Channel Activity by GRK2

Extending their accepted role in downregulating GPCRs from the cell membrane following GPCR activation, GRK shows an additional novel role, to rapidly control GPCRs activation of effectors that depend on the G protein βγ subunits (Gβγ), independent of their catalytic activity. GPCR-coupled potassium channels (GIRK) are found in excitable tissues such as neurons, heart, and endocrine organs, where they are known to decrease cells’ excitability following their activation by Gi/o-coupled GPCRs. In these tissues, GIRK participate in signaling systems that demand a precise temporal control, such as the regulation of heart rate and synaptic activity. While GPCRs activation can be prolonged by agonists, a constrained temporal response of GIRK channel activity can be achieved by GRKs capable of binding Gβγ subunit (GRK2 and 3). Simultaneously with GPCR activation, GRK2 binds the free Gβγ subunits through its pleckstrin homology domain immediately ceasing GIRK channel activity, in a process of fast desensitization. GIRK fast desensitization occurs with the mass action of cytosolic GRK2 recruited to the cell membrane upon receptor activation which appears simultaneously with channel current desensitization. Interestingly, GRK-mediated desensitization of GIRK currents is mediated by many but not all different Gi/o-linked GPCRs. The question whether a GPCR-mediated GRK fast desensitization relies on a specific Gβγ subunits pair coupled to a specific receptor, or on a direct precou-pling of GRK to a specific subset of the GPCRs is still an open question.