A decade since their discovery, the K2P channels are recognized as pathways dedicated to regulated background leakage of potassium ions that serve to control neuronal excitability. The recent identification of protein partners that directly interact with K2P channels (SUMO, 14-3-3 and Vpu1) has exposed new regulatory pathways. Reversible linkage to SUMO silences K2P1 plasma membrane channels; phosphorylation of K2P3 enables 14-3-3 binding to affect forward trafficking, whereas it decreases open probability of K2P2; and, Vpu1, an HIV encoded partner, mediates assembly-dependent degradation of K2P3. An operational strategy has emerged: tonic inhibition of K2P channels allows baseline neuronal activity until enhanced potassium leak is required to suppress excitability
