Insulin activates PI3K, which phosphorylates PIP₂ on position 3′ in the inositol ring, generating PIP₃. The lipid phosphatase PTEN antagonizes this by dephosphorylating PIP₃ to generate PIP₂. PIP₃ accumulation leads to activation of K_ATP channels and, thus, to potassium outflow. This leads to membrane hyperpolarization and silencing of the neuron. Three different mechanisms for channel opening have been suggested: (i) PIP₃ binding to the Kir6.2 subunit of the potassium channel increases the probability that the channel is open, which indirectly lowers inhibition by ATP; (ii) PIP₃ competes with ATP for binding to the Kir6.2 subunit, thereby lowering ATP’s ability to close the channel; and (iii) PIP₃ activates degradation of the local actin cytoskeleton. Also, activation of proteins downstream in the insulin cascade such as PDK1, AKT, glycogen synthase kinase 3 (GSK3), or mammalian target of rapamycin (mTOR) may be involved in insulin’s ability to regulate K_ATP channel opening.