Cerebral Vascular KIR2.x Channels are Distinctly Regulated by Membrane Lipids and Hemodynamic Forces.

Abstract

This study examined membrane lipid (phosphatidylinositol‐bis‐phosphate (PIP2) and cholesterol) regulation of cerebral arterial KIR and whether these signaling molecules enable distinct channel pools to uniquely sense hemodynamic forces. Endothelial and smooth muscle cells were freshly isolated from rat cerebral arteries; patch‐clamp electrophysiology, Q‐PCR and immunohistochemistry delineated KIR channel activity and expression. Electrophysiology revealed a Ba2+‐sensitive KIR current in smooth muscle and endothelial cells, while Q‐PCR and immunohistochemistry confirmed KIR2.x mRNA and protein expression respectively. Each cellular pool of KIR channels was sensitive to particular membrane lipids and hemodynamic forces. Endothelial KIR responded dynamically to PIP2 manipulations, and laminar flow activated this channel pool in a PIP2 dependent manner. In contrast, smooth muscle KIR reacted to cholesterol perturbations, and pressure stimuli (e.g. hyposmotic challenge or negative pressure application) modulated this channel pool in a cholesterol dependent manner. The flow and pressure sensitivity of KIR channels was confirmed in intact cerebral arteries using vessel myography. In summary, while both vascular cell types express KIR2.x channels, each pool is distinctly regulated by membrane lipids and hemodynamic stimuli. This emerging picture of KIR regulation advances our mechanistic understanding of how hemodynamic forces interact to control arterial tone development.Support or Funding InformationThis research was supported by an operating grant from the Canadian Institute of Health Research. DG Welsh is Rorabeck Chair of Molecular Neuroscience and Vascular Biology at the University of Western Ontario.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.