alcohol, could be mechanistically referred to as positive allosteric modulators (PAMs). PAMs are molecules that cannot activate the channel on their own but increase the efficacy or potency of an agonist, i.e., PIP2. For example, benzodiazepine is a PAM for GABAA receptors; it does not activate GABAA receptors but shifts the EC50 for agonist, i.e., GABA, activation55. However, the endogenous levels of PIP2 are low relative to the sensitivity of GIRK channels, resulting in a small basal channel activity. GIRK channels are considered to have a relatively low affinity for PIP2, compared to constitutively active Kir2.1 channels56. Consistent with this, the EC50 for activation of GIRK2 with diC8-PIP2 is ~25 μM, which compares to a 10-fold lower EC50 of ~2 μM for Kir2.157. Interestingly, the GIRK channel activators, i.e., Gβγ, alcohol and cholesterol, do not alter the levels of PIP2 but instead change the apparent affinity of the channel for PIP2. The shift in apparent PIP2 affinity with these activators likely occurs through allosteric changes in the channel that alter the rates of association and dissociation of PIP2. On the other hand, stimulation of GPCRs that couple to Gq G proteins can reversibly lower the levels of membrane PIP2, leading
