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Proc Natl Acad Sci U S A. 2018 Apr 10;115(15):E3569-E3577. doi: 10.1073/pnas.1800201115. Epub 2018 Mar 26.

Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion.

Author information

1
Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405.
2
Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405; Mark.Nelson@uvm.edu.
3
Institute of Cardiovascular Sciences, University of Manchester, M13 9PL Manchester, United Kingdom.

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.

KEYWORDS:

GPCR; PIP2; cerebral blood flow; neurovascular coupling; potassium channels

PMID:
29581272
PMCID:
PMC5899484
DOI:
10.1073/pnas.1800201115
[Indexed for MEDLINE]
Free PMC Article

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