Inwardly Rectifying Potassium Channels: Regulators of Myogenic Tone in Cerebrovascular Smooth Muscle
Abstract
In cerebral arteries, inwardly rectifying potassium channels (KIR) contribute to smooth muscle hyperpolarization to control arterial diameter and tone. Emerging evidence highlighted their regulation by pressure, though the underlying mechanism remains unclear. This thesis explored this concept through examination of KIR channels in mouse and rat cerebral vascular smooth muscle (VSM). Experiments progressed from isolated cells to whole animals, employing electrophysiology, immunocytochemistry, proximity ligation assay, and arterial spin-labelling MRI techniques. Initial experiments indicated that KIR activity persists beyond KIR2.1 knockout in smooth muscle, clarifying their molecular composition. Our subsequent study identified key structural components involved in KIR mechanosensing. Disruption of the cytoskeleton impaired the KIR pressure response in isolated cells. Syntrophin and caveolin-1, protein intermediates known to facilitate actin-channel interactions, were both identified in VSM cells and found co-localized with KIR2.2. In summary, this thesis provides insight into the composition, function, and associated mechanotransduction complex of KIR channels in VSM.