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Cited by 149Ion Channels and ReceptorsBarrier Structure and Function StudiesIon channel regulation and function

PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells

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Harraz, Osama F, Longden, Thomas A, Hill-Eubanks, David, Nelson, Mark T·2018·eLife
DOI 10.7554/elife.38689PMC PMC6117155
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Abstract

We recently reported that the inward-rectifier Kir2.1 channel in brain capillary endothelial cells (cECs) plays a major role in neurovascular coupling (NVC) by mediating a neuronal activity-dependent, propagating vasodilatory (hyperpolarizing) signal. We further demonstrated that Kir2.1 activity is suppressed by depletion of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2). Whether cECs express depolarizing channels that intersect with Kir2.1-mediated signaling remains unknown. Here, we report that Ca2+/Na+-permeable TRPV4 (transient receptor potential vanilloid 4) channels are expressed in cECs and are tonically inhibited by PIP2. We further demonstrate that depletion of PIP2 by agonists, including putative NVC mediators, that promote PIP2 hydrolysis by signaling through Gq-protein-coupled receptors (GqPCRs) caused simultaneous disinhibition of TRPV4 channels and suppression of Kir2.1 channels. These findings collectively support the concept that GqPCR activation functions as a molecular switch to favor capillary TRPV4 activity over Kir2.1 signaling, an observation with potentially profound significance for the control of cerebral blood flow.

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  • TRPV4 channel is inhibited by PI(4,5)P2 and opens when PI(4,5)P2 levels drop, opposite to Kir2.1; depletion of PI(4,5)P2 by Gαq-PLCβ1 agonists can cause simultaneous closure of Kir2.1 and opening of TRPV4 in endothelial cells.

    “The Ca2+/Na+ TRPV4 (transient receptor potential vanilloid 4) channel is inhibited by PI(4,5)P2 and opens when PI(4,5)P2 levels drop, the opposite to Kir2.1 channels. The depletion of PI(4,5)P2 by agonists such as prostaglandin E2, ATP or acetylcholine that signal through Gαq-PLCβ1 can therefore cause a simultaneous closure of Kir2.1 channels and the opening of TRPV4 channels as observed in”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [117]

    The Introduction and the Results section on GqPCR signaling state that PIP2 inhibits TRPV4 while sustaining Kir2.1 activity, and that PGE2 produces the proposed simultaneous effects in mouse brain capillary endothelial cells (pages not provided). The same Results section reports that carbachol, a muscarinic agonist, also produces both effects. But ATP inhibited Kir2.1 without affecting TRPV4, so the paper does not support including ATP among agonists that cause simultaneous Kir2.1 closure and TRPV4 opening; it also does not directly report that result for acetylcholine itself. (LLM, conf=0.91)

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Authors
Harraz, O. F., Longden, T. A., Hill-Eubanks, D., & Nelson, M. T.
Affiliations
  • University of Vermont (US)
  • Department of Pharmacology, University of Vermont, Burlington, United States
Corresponding author
Nelson, Mark T
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2018-08-07
Volume
7
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.38689
PMC
PMC6117155
OpenAlex
W2885463086
Cited by
149
References
2
Citations by year
2026: 15 · 2025: 10 · 2024: 15 · 2023: 24 · 2022: 23 · 2021: 22 · 2020: 22 · 2019: 16 · 2018: 2
FWCI
10.01
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Research Explorer (The University of Manchester) (submittedVersion, cc-by)
  • Health Research Alliance (cc-by)
Funders
  • American Heart Association (Postdoctoral fellowship 17POST33650030, Scientist Development Grant 17SDG33670237)
  • National Institutes of Health (P01-HL-095488, 4P20 GM103644/4-5 to the Vermont Center on Behavior and Health, P30-GM-103498 to the COBRE imaging facility at UVM College of Medicine, R01-HL-121706, R37-DK-053832, 7UM-HL-1207704, R01-HL-131181)
  • The Totman Medical Research Trust
  • Fondation Leducq
  • European Union's Horizon 2020 Research and Innovation Programme (Grant agreement No 666881 SVDs@target)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
TRPV4 channel, phosphatidylinositol 4,5-bisphosphate, brain microvascular endothelial cells, Kir2.1, inwardly rectifying potassium channels, neurovascular coupling, Gq protein-coupled receptors, cerebral autoregulation, vasodilation
MeSH terms
Animals, Brain, Mice, Inbred C57BL, Signal Transduction, Mice, Knockout, Phosphatidylinositol 4,5-Diphosphate, Potassium Channels, Inwardly Rectifying, Endothelial Cells, GTP-Binding Protein alpha Subunits, Gq-G11, TRPV Cation Channels

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