N-glycosylation modulates the inactivation kinetics of the Kv3.4 ion channel

In our previous study, when mapping the kinetics of all 40 genetic subtypes of the voltage-gated potassium (Kv) family of ion channels, we observed significant heterogeneity in the inactivation delay of Kv3.4. Kv3.4 enables high-frequency firing in excitable cells and is linked to disorders such as Alzheimer's disease, epilepsy, chronic pain, and cardiovascular disease. In this study, we found that N-glycosylation, a co- and post-translational process of adding glycans branches to proteins, is a key mechanism that causes heterogeneity in the inactivation delay of Kv3.4 ion channel. Additionally, we discovered that changes in glucose availability directly affect N-glycosylation and the kinetics of Kv3.4, along with other N-glycosylated Kvs, making glucose a key regulator of Kv activity and, consequently, cell excitability. We propose that disruptions in N-glycosylation of Kv3.4 ion channels may play a role in neurological disorders linked to impaired glucose metabolism.