Exploiting structure-function of potassium channels for modulation

This project aims to identify approaches for modulating the activity of select potassium (K+) ion channels. A diverse family of K+ channels controls electrical signaling throughout the body, critical for myriad physiological processes. Consequently, K+ channel dysfunction can result in a wide-ranging pathology, both acquired and heritable. In many cases, including rare potassium channelopathies, there are no known targeted therapies, but as the dysfunctional gene and protein is known, these disorders represent tractable biomedical challenges. Here we seek to dissect how key structural properties of select K+ channels govern their functions, and how we can exploit these physical characteristics with novel chemical biology. This program combines studies of three K+ channels, KATP (ATP-sensitive potassium) channels containing the key SUR2 subunit, Kir2.1 channels, and the mechanosensitive TREK subfamily of K2P channels. We will combine patch clamp electrophysiology, with molecular biology and protein engineering approaches, unbiased genetic mutational screening, molecular evolution approaches, and experimental and computational structural biology to define new protein-based and small molecule modulators of these channels. These directions include developing engineered split-SUR2 subunits capable of restoring KATP function in vivo; attempts to identify rescue mutations to compensate for disease-causing variants in Kir2.1; and characterization of a promiscuous drug binding site and the role of the distinctive extracellular cap domain in K2P channels. These studies will provide new insights to how KATP and Kir channels assemble and will identify clinically applicable gene-therapy technologies to treat orphan channelopathies in the future. Further, they will reveal how unique structural features bestow K2P channels with defining pharmacological and functional characteristics. Collectively, over the next five years these studies will build on basic understandings of how these K+ channels form and function and leverage these insights to find new tools to correct molecular dysfunction. Project Number: 1R35GM162430-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Conor McClenaghan | Institution: RUTGERS BIOMEDICAL AND HEALTH SCIENCES, Newark, NJ | Award Amount: $392,500 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - E Study Section[MRAE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11269841