期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 15, 页码 E3569-E3577出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1800201115
关键词
potassium channels; GPCR; cerebral blood flow; neurovascular coupling; PIP2
资金
- American Heart Association [17POST33650030, 17SDG33670237]
- United Leukodystrophy Foundation
- Totman Medical Research Trust
- Fondation Leducq
- European Union [666881]
- National Institutes of Health [R01-HL-136636, 4P20 GM103644/4-5, P30-GM-103498, P01-HL-095488, R01-HL-121706, R37-DK-053832, 7UM-HL-1207704, R01-HL-131181]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL131181, R01HL121706, P01HL095488, R01HL136636] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK053832, R37DK053832] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM103644, P30GM103498] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD010583] Funding Source: NIH RePORTER
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 G(q) protein-coupled receptors (G(q)PCRs) cripples capillary-to-arteriole signal transduction in vitro and in vivo, highlighting the potential regulatory linkage between G(q)PCR-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.
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