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Edited by Arthur Karlin, College of Physicians and Surgeons, Columbia University, New York, NY, and approved March 1, 2018 (received for review January 8, 2018)
Significance
Capillaries, the smallest blood vessels, mediate the on-demand delivery of oxygen and nutrients required to support the function of active cells throughout the brain. But how blood flow is directed to cells in active brain regions to satisfy their energy needs is poorly understood. We demonstrate that the plasma membrane phospholipid, PIP2, is fundamental to sustaining the activity of inwardly rectifying potassium channels—the molecular feature that allows capillary endothelial cells to sense ongoing neuronal activity and trigger an increase in local blood flow. We further show that chemical factors released in the brain, including those associated with neuronal activity, cause changes in the levels of PIP2, thereby altering endothelial potassium channel signaling and controlling cerebral blood flow.
Abstract
Brain capillaries play a critical role in sensing neural activity and translating it into dynamic changes in cerebral blood flow to serve the metabolic needs of the brain. The molecular cornerstone of this mechanism is the capillary endothelial cell inward rectifier K+ (Kir2.1) channel, which is activated by neuronal activity–dependent increases in external K+ concentration, producing a propagating hyperpolarizing electrical signal that dilates upstream arterioles. Here, we identify a key regulator of this process, demonstrating that phosphatidylinositol 4,5-bisphosphate (PIP2) is an intrinsic modulator of capillary Kir2.1-mediated signaling. We further show that PIP2 depletion through activation of Gq protein-coupled receptors (GqPCRs) cripples capillary-to-arteriole signal transduction in vitro and in vivo, highlighting the potential regulatory linkage between GqPCR-dependent and electrical neurovascular-coupling mechanisms. These results collectively show that PIP2 sets the gain of capillary-initiated electrical signaling by modulating Kir2.1 channels. Endothelial PIP2 levels would therefore shape the extent of retrograde signaling and modulate cerebral blood flow.
Footnotes
- ↵1To whom correspondence should be addressed. Email: Mark.Nelson{at}uvm.edu.
Author contributions: O.F.H. and M.T.N. designed research; O.F.H., T.A.L., and F.D. performed research; O.F.H., T.A.L., and F.D. analyzed data; and O.F.H., T.A.L., F.D., D.H.-E., and M.T.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1800201115/-/DCSupplemental.
Published under the PNAS license.
Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion
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