GIRK channels are members of a large family of inwardly rectifying potassium channels (Kir1 – Kir7). The term “inward rectification” refers to a change in slope of the current-voltage relationship at the reversal potential (i.e. the zero current level, which occurs at the equilibrium potential for K+ - EK). Therefore the outward current is smaller (but not zero) than the inward current (Figure 1A), due to occlusion of the central pore by intracellular Mg2+ and polyamines3. Under physiological conditions the resting membrane potential of a typical neuron is positive to EK, and the small outward K+ current through GIRK channels decreases the excitability of a neuron (Figure 1A, large arrow). Different types of neurotransmitters, such as acetylcholine, dopamine, opioids, serotonin, somatostatin, adenosine and GABA, activate these channels by stimulating their cognate G protein-coupled receptors (GPCRs), which in turn couple specifically to pertussis toxin (PTX) sensitive heterotrimeric G proteins that activate GIRK channels4. Whether the activated Gα subunit or Gβγ dimer directly opened GIRK channels was the focus of an animated debate in the 1980s (see Box 1). Now, a preponderance
