KCNE ancillary subunits dictate the surface composition and density of voltage-gated potassium channels

Voltage-gated potassium (Kv) channels play critical roles in regulating membrane excitability, resting membrane potential, action potential morphology, firing patterns, and neurotransmitter release. Kv channels are the most diverse class of voltage-gated ion channels, augmented by heteromerization of the numerous pore-forming (α) subunits, alternative-splicing, and association with non pore-forming ancillary (β) subunits. Excitable cells each use multiple Kv channel subunit combinations to generate the specific electrical profiles essential to each functional niche. Despite the importance to excitable cell physiology of factors governing the composition, forward trafficking, and internalization of Kv channels, many key issues in Kv channel ontogeny remain unresolved. Of particular interest are mechanisms determining the tendency of heteromeric Kv complexes to form versus homomeric complexes, and the mediation of internalization once Kv channels reach the plasma membrane. Using a combination of electrophysiological, biochemical and microscopy analyses, we highlight the role played by the KCNE family of β subunits in Kv channel secretory and endocytic trafficking. First, we show that three sites on KCNE1 dictate the clathrin and dynamin-dependent internalization (DDI) of the channel complex formed by KCNQ1 and KCNE1, generating the slow-activating cardiac repolarization K+ current (IKs) (Xu et al., 2009). One of these sites, serine 102, has long been known to be a Protein Kinase C (PKC) phosphorylation site, mediating the down-regulation of I Ks through an heretofore unknown mechanism. In a follow-up study, we solve this long-standing conundrum by showing that PKC induces the down-regulation of IKs currents through DDI, via serine 102 (Kanda, 2011). Next, we focus on forward trafficking. Three α subunits, Kv1.4, Kv3.3, and Kv3.4, generate currents that decay rapidly, due to an N-terminal 'ball' domain that blocks the channel pore following activation, referred to as N-type inactivation. Here, we show that KCNE1 and KCNE2 suppress 'N-type' Kv channel currents by trapping the channel complexes early in the secretory pathway, preventing their forward trafficking. Furthermore, in a companion study, we show that this trapping is prevented by co-assembly of N-type and intra-subfamily delayed rectifier α subunits, promoting the surface expression of mixed α-α complexes. These data illustrate that by acting as both molecular matchmakers and endocytic chaperones, KCNE subunits dictate the surface expression of Kv channels and govern cellular excitability.