A molecular dissection of BK channelopathy in neurological disorders

Project Summary The KCNMA1-encoded BK Slo1 potassium channel plays a pivotal role in regulating neural activity and neurotransmitter release. KCNMA1 variants, or channelopathies, have been increasingly identified in patients with neurological disorders, representing a spectrum of clinical manifestations, ranging from epilepsy, neurodevelopmental anomalies to movement disorders. Given this heterogeneity, precision medicine emerges as a vital need for tailored diagnosis and treatment. To meet this challenge, our multidisciplinary team hypothesizes that different KCNMA1 variants influence distinct molecular gating mechanisms, leading to differential alterations of neuronal activities and varied clinical presentations. To test this hypothesis and to lay a solid foundation for future investigation of more KCNMA1 channelopathies, we aim to unravel the genotype- phenotype connections of three gain-of-function (GOF) KCNMA1 variants, D434G, A532V and N536H. Our previous publications and preliminary studies show that these GOF variants alter distinct BK channel gating mechanisms at the molecular level, and the patients show different clinical manifestations. In this proposal, we will closely compare the molecular gating mechanisms (Aim 1), neuronal activities and knock-in mouse behaviors (Aim 2) of these three GOF variants. In addition, we will strategically design and administer variant-specific modulators to either mimic or mitigate KCNMA1 channelopathies to further test the variant-specific alterations of neurological phenotypes. The variant-specific inhibitors may lead to the development of drugs with more specificity and thus with minimal effect on people with normal BK channels. Through molecular analysis, mouse model development, and innovative drug design, this research aspires to revolutionize our understanding of KCNMA1 channelopathies and accelerate the advancement of precision medicine solutions.