Date of Award
Doctor of Philosophy (PhD)
Miao Zhang, Ph.D., Chair
Kamaljit Kaur, Ph.D.
Meng Cui, Ph.D.
Sun Yang, Ph.D.
The Ca2+-activated potassium channels KCa channels are a unique family of potassium channels activated by intracellular calcium. KCa channels are critical for maintaining K+ homeostasis and modulate several physiological processes, from the firing properties of neurons to the control of the transmitter release. The Ca2+ sensitivity of these channels allows intracellular Ca2+ to regulate the electrical activity of the cell membrane. Increased Ca2+ sensitivity of KCa channels caused by gain of function mutations (GOF) in the KCNN genes results in a broad spectrum of human channelopathies, including Zimmermann- Laband syndrome (ZLS), idiopathic non-cirrhotic portal hypertension (INCPH), and hereditary xerocytosis (HX). The impact of dysfunctional KCa2.3/KCa3.1 channels on human health has not been well documented. In this dissertation, I used inside-out patch clamp recordings to measure the apparent Ca2+ sensitivity of KCa2.3 and KCa3.1 heterologously expressed in HEK293 cells. Wild-type KCa2.3 channels have a Ca2+ EC50 value of ∼0.3 μM, while the apparent Ca2+ sensitivity of wild-type KCa3.1 channels is ∼0.27 μM. The equivalent mutations related to the ZLS and INCPH in the S45A/S45B helices increased the apparent Ca2+ sensitivity of both KCa2.3 & KCa3.1 channel subtypes. However, the equivalent mutations related to the HX in HA/HB helices of KCa2.3 and KCa3.1 affected their apparent Ca2+ sensitivity differently. AP14145 reduced the apparent Ca2+ sensitivity of the hypersensitive mutant KCa2.3 channels. The results of my Ph.D. project would suggest the potential therapeutic usefulness of negative gating modulators as a novel target in these channelopathy-causing mutations. At the same time would guide us to design more potent and subtype-selective positive modulators targeting these channels.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Orfali, RS. Genetic Mutations of KCa2.3 and KCa3.1 Channels Affect Ca2+ Sensitivity. [dissertation]. Irvine, CA: Chapman University; 2023. https://doi.org/10.36837/chapman.000489
Medicinal and Pharmaceutical Chemistry Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Pharmaceutics and Drug Design Commons