1. Neuroscience
  2. Structural Biology and Molecular Biophysics

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

  1. Osama F Harraz
  2. Thomas Andrew Longden
  3. David Hill-Eubanks
  4. Mark T Nelson  Is a corresponding author
  1. University of Vermont, United States
https://doi.org/10.7554/eLife.38689
Share this article
Cite this article
  1. Osama F Harraz
  2. Thomas Andrew Longden
  3. David Hill-Eubanks
  4. Mark T Nelson
(2018)
PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells
eLife 7:e38689.
https://doi.org/10.7554/eLife.38689
  2. Download BibTeX
  3. Download .RIS

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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting source data files.

The following previously published data sets were used

Article and author information

Author details

  1. Osama F Harraz

    Department of Pharmacology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2061-1100

  2. Thomas Andrew Longden

    Department of Pharmacology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. David Hill-Eubanks

    Department of Pharmacology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Mark T Nelson

    Department of Pharmacology, University of Vermont, Burlington, United States
    For correspondence
    Mark.Nelson@uvm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6608-8784

Funding

American Heart Association (Postdoctoral fellowship 17POST33650030)

  • Osama F Harraz

National Institutes of Health (R37-DK-053832)

  • Mark T Nelson

National Institutes of Health (7UM-HL-1207704)

  • Mark T Nelson

National Institutes of Health (R01-HL-131181)

  • Mark T Nelson

American Heart Association (Scientist Development Grant 17SDG33670237)

  • Thomas Andrew Longden

National Institutes of Health (P01-HL-095488)

  • Mark T Nelson

National Institutes of Health (4P20 GM103644/4-5 to the Vermont Center on Behavior and Health)

  • Thomas Andrew Longden

The Totman Medical Research Trust

  • Mark T Nelson

Fondation Leducq

  • Mark T Nelson

European Union's Horizon 2020 Research and Innovation Programme (Grant agreement No 666881 SVDs@target)

  • Mark T Nelson

National Institutes of Health (P30-GM-103498 to the COBRE imaging facility at UVM College of Medicine)

  • Mark T Nelson

National Institutes of Health (R01-HL-121706)

  • Mark T Nelson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All procedures involving animals received prior approval from the University of Vermont Institutional Animal Care and Use Committee (IACUC, protocol # 14-063 and 16-010). Animals were euthanized by intraperitoneal injection of sodium pentobarbital (100 mg/kg) followed by rapid decapitation. Every effort was made to minimize suffering of animal subjects.

Copyright

© 2018, Harraz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 6,538
    views
  • 701
    downloads
  • 108
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Osama F Harraz
  2. Thomas Andrew Longden
  3. David Hill-Eubanks
  4. Mark T Nelson
(2018)
PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells
eLife 7:e38689.
https://doi.org/10.7554/eLife.38689

Share this article

https://doi.org/10.7554/eLife.38689

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Coupling of saccade plans to endogenous attention during urgent choices

    Allison T Goldstein, Terrence R Stanford, Emilio Salinas
    Research Article

    The neural mechanisms that willfully direct attention to specific locations in space are closely related to those for generating targeting eye movements (saccades). However, the degree to which the voluntary deployment of attention to a location necessarily activates a corresponding saccade plan remains unclear. One problem is that attention and saccades are both automatically driven by salient sensory events; another is that the underlying processes unfold within tens of milliseconds only. Here, we use an urgent task design to resolve the evolution of a visuomotor choice on a moment-by-moment basis while independently controlling the endogenous (goal-driven) and exogenous (salience-driven) contributions to performance. Human participants saw a peripheral cue and, depending on its color, either looked at it (prosaccade) or looked at a diametrically opposite, uninformative non-cue (antisaccade). By varying the luminance of the stimuli, the exogenous contributions could be cleanly dissociated from the endogenous process guiding the choice over time. According to the measured time courses, generating a correct antisaccade requires about 30 ms more processing time than generating a correct prosaccade based on the same perceptual signal. The results indicate that saccade plans elaborated during fixation are biased toward the location where attention is endogenously deployed, but the coupling is weak and can be willfully overridden very rapidly.

    1. Neuroscience

    Difficulty in artificial word learning impacts targeted memory reactivation and its underlying neural signatures

    Arndt-Lukas Klaassen, Björn Rasch
    Research Article

    Sleep associated memory consolidation and reactivation play an important role in language acquisition and learning of new words. However, it is unclear to what extent properties of word learning difficulty impact sleep associated memory reactivation. To address this gap, we investigated in 22 young healthy adults the effectiveness of auditory targeted memory reactivation (TMR) during non-rapid eye movement sleep of artificial words with easy and difficult to learn phonotactical properties. Here, we found that TMR of the easy words improved their overnight memory performance, whereas TMR of the difficult words had no effect. By comparing EEG activities after TMR presentations, we found an increase in slow wave density independent of word difficulty, whereas the spindle-band power nested during the slow wave up-states – as an assumed underlying activity of memory reactivation – was significantly higher in the easy/effective compared to the difficult/ineffective condition. Our findings indicate that word learning difficulty by phonotactics impacts the effectiveness of TMR and further emphasize the critical role of prior encoding depth in sleep associated memory reactivation.

    1. Neuroscience

    Age-related decline in blood-brain barrier function is more pronounced in males than females in parietal and temporal regions

    Xingfeng Shao, Qinyang Shou ... Danny JJ Wang
    Research Article

    The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), and shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here, we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8–92 years old, using a non-invasive diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI technique. We found that the pattern of BBB kw decline with aging varies across brain regions. Moreover, results from our DP-pCASL technique revealed a remarkable decline in BBB kw beginning in the early 60 s, which was more pronounced in males. In addition, we observed sex differences in parietal and temporal regions. Our findings provide in vivo results demonstrating sex differences in the decline of BBB function with aging, which may serve as a foundation for future investigations into perfusion and BBB function in neurodegenerative and other brain disorders.