Date of Award
Doctor of Philosophy (PhD)
Dr. Miao Zhang
Dr. Sun Yang
Dr. Keykavous Parang
Dr. Meng Cui
Small-conductance Ca2+-activated potassium channels (KCa2.x) family is widely expressed in neurons, the heart, and endothelial cells. KCa2.x channels are named small conductance Ca2+-activated potassium channels due to their comparatively low single-channel conductance and are activated solely by rises in intracellular Ca2+. The family has three subtypes: KCa2.1, KCa2.2, and KCa2.3, encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. KCa2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. Small-conductance Ca2+-activated potassium channels subtype 2 (KCa2.2, also called SK2) is a promising drug target for spinocerebellar ataxias (SCAs), genetic disorders with no available treatment. Heterozygous genetic mutations of KCa2.2 channels have been associated with autosomal dominant neurodevelopmental disorders, including cerebellar ataxia and tremor in humans and rodents. The structure-function studies of the rat KCa2.2 channel using seven pathogenic mutations (I289N, I360M, Y362C, G363S, I389V, L174P, and L433P) associated with these disorders were performed to investigate the insight of these disorders related to KCa2.2. The dominant mutations negatively suppressed and completely abolished the activity of the co-expressed KCa2.2_WT channel, suggesting that these mutations may be causative in neurodevelopmental disorders. Additionally, the co-expression of the KCa2.2_I289N and the KCa2.2_WT channels reduced the apparent Ca2+ sensitivity compared with the KCa2.2_WT channel rescued by a KCa2.2 positive modulator. A positive allosteric modulator of KCa2.2/KCa2.3 channels (compound 2q) has been developed, and a method for quantitating it in mouse plasma has been validated using FDA guidelines. The developed assay is suitable for preclinical pharmacokinetic-pharmacodynamic studies of 2q as a potential drug candidate for ataxias.
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Rahman, M.A. Pharmacological and Pharmacokinetic Studies of a KCa2.2 Positive Allosteric Modulator. [dissertation]. Irvine, CA: Chapman University; 2023. https://doi.org/10.36837/chapman.000498
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