Thursday, November 21, 2024
11/21/2024
This project aims at pinpointing the molecular basis for the regulation of the dynamic kinetic properties of two members of the KV7 family, namely KV7.2 and KV7.3. These proteins are voltage- gated, potassium-selective (KV) channels encoded by the KCNQ genes. We have reported that the heteromeric KV7.2/KV7.3 channel becomes resilient to close (be deactivated) as it remains opened (activated). This finding let us to postulate that this heteromeric channel can operate in at least two different modes of activity. We also found that these modes are adopted by the channel as a function of its own activity. We initially distinguished these modes by their deactivation rate. Following a short period of activity, channels display a faster deactivation kinetic than when channels are steadily held activated. This decrease in the deactivation rate can be also seen when KV7 channels are activated at negative membrane potentials like those observed in excitable cells at resting conditions. This suggests that KV7 channels operate in the “slow- deactivating” mode under physiological conditions, rather than in the “fast-deactivating” mode which is typically observed experimentally. Here, we propose that the decrease in the rate of deactivation is a manifestation of open/activated channel stabilization and that is essential for the physiological function of KV7 channels. Further, we found that the KV7 channel agonist known as retigabine (ezogabine) is able to discriminate between these modes of activity. We found that retigabine makes the “slow-deactivating” mode even slower, while having no effect on the “fast- deactivating” mode. Furthermore, we found that depletion of the phosphoinositide PI(4,5)P2 from the membrane impairs the stabilization of the open channel. Therefore, we propose that modal activity is the target of regulation by PI(4,5)P2. This proposal aims at further understanding modal activity in KV7 channels. This proposal also aims at pinpointing residues in KV7.2 and KV7.3 channels that are critically involved in modal activity. Funding of this work is critically important to further our understanding of the physiology of KV7 channels. They are intimately involved in cellular electrical activity in the nervous, cardiovascular and gastrointestinal systems. Today, it has been well established that KV7 channels are at the center of many cellular pathways including those involving G protein-coupled receptors tied to Gq proteins. In fact, mutations in KCNQ genes lead to several types of disorders including infantile epilepsy, long QT syndromes, and chronic pain. These disorders combined affect 7% of the U.S. population per NIH estimates. To effectively address these and understand their physiology, pharmacology and pathophysiology, we aim with this proposal at gaining detailed comprehensive knowledge of the activity of KV7 channels.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
