PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/38689 |
| _version_ | 1811235918422474752 |
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| author | Osama F Harraz Thomas A Longden David Hill-Eubanks Mark T Nelson |
| author_facet | Osama F Harraz Thomas A Longden David Hill-Eubanks Mark T Nelson |
| author_sort | Osama F Harraz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:00:06Z |
| format | Article |
| id | doaj.art-36a3959b2839416b96d944daee300602 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:00:06Z |
| publishDate | 2018-08-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj.art-36a3959b2839416b96d944daee3006022022-12-22T03:33:52ZengeLife Sciences Publications LtdeLife2050-084X2018-08-01710.7554/eLife.38689PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cellsOsama F Harraz0https://orcid.org/0000-0003-2061-1100Thomas A Longden1David Hill-Eubanks2Mark T Nelson3https://orcid.org/0000-0002-6608-8784Department of Pharmacology, University of Vermont, Burlington, United StatesDepartment of Pharmacology, University of Vermont, Burlington, United StatesDepartment of Pharmacology, University of Vermont, Burlington, United StatesDepartment of Pharmacology, University of Vermont, Burlington, United States; Institute of Cardiovascular Sciences, Manchester, United KingdomWe 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.https://elifesciences.org/articles/38689TRPV4neurovascular couplingPIP2Kir2.1GPCRbrain capillaries |
| spellingShingle | Osama F Harraz Thomas A Longden David Hill-Eubanks Mark T Nelson PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells eLife TRPV4 neurovascular coupling PIP2 Kir2.1 GPCR brain capillaries |
| title | PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells |
| title_full | PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells |
| title_fullStr | PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells |
| title_full_unstemmed | PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells |
| title_short | PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells |
| title_sort | pip2 depletion promotes trpv4 channel activity in mouse brain capillary endothelial cells |
| topic | TRPV4 neurovascular coupling PIP2 Kir2.1 GPCR brain capillaries |
| url | https://elifesciences.org/articles/38689 |
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