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Capillary endothelial G q protein‐coupled receptors and PIP 2 toggle signaling between TRPV4 and Kir2 channels in the brain
Author(s) -
Harraz Osama F,
Longden Thomas A,
Dabertrand Fabrice,
Nelson Mark T
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.681.1
Subject(s) - trpv4 , transient receptor potential channel , chemistry , phosphatidylinositol , receptor , agonist , inward rectifier potassium ion channel , biophysics , intracellular , voltage dependent calcium channel , inositol trisphosphate , microbiology and biotechnology , ion channel , inositol , signal transduction , calcium , biochemistry , biology , organic chemistry
The ion channel composition of capillaries is not known. Using freshly dissociated capillary endothelial cells (cECs) from mouse brain, we measured currents through strong inward rectifier K + (Kir2.1) channels and through transient receptor potential vanilloid (TRPV4) channels. We have proposed that Kir2.1 and TRPV4 channels are involved in electrical and calcium signaling, respectively, to transmit signals from cECs to upstream arterioles. We tested the hypothesis that these two channel types are functionally linked through phosphatidylinositol 4,5‐bisphosphate (PIP 2 ). We found that intracellular PIP 2 or ATP had opposite effects on TRPV4 and Kir2.1 currents, with PIP 2 or ATP suppressing TRPV4 channel activity and conversely being essential for Kir2.1 activity. The level of PIP 2 is controlled by the activity of G q protein‐coupled receptors (G q PCRs), which hydrolyze PIP 2 to produce inositol 1,4,5‐triphosphate (IP 3 ) and diacyglycerol (DAG). We therefore tested the effects of prostaglandin E 2 (PGE 2 ; an agonist of the G q PCR EP 1 ), which has been implicated in neurovascular coupling, on TRPV4 and Kir2.1 currents in cECs, with the expectation of divergent effects on the two conductances. Indeed, when measured simultaneously in the same cECs, PGE 2 increased TRPV4 currents with half‐time (t 0.5 ) of 3.5 minutes and decreased Kir2.1 currents with a t 0.5 of 5.3 minutes. In conclusion, the present study supports the concept that PIP 2 tonically inhibits TRPV4 channels and activates Kir2.1 channels in the brain capillary endothelium. G q PCR activation therefore acts as a molecular switch that alters the balance between electrical (Kir2.1) and Ca 2+ (TRPV4) signaling, which might change the signaling modality to upstream penetrating arterioles, and would have profound effects on the control of blood flow into the brain. Support or Funding Information Supported by the NIH, Fondation Leducq and EC Horizon 2020 grants.