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TRPV4‐Mediated Ion Transport in the Choroid Plexus
Author(s) -
Preston Daniel,
Simpson Stefanie,
Danko Caleb,
Schroten Horst,
Schwerk Christian,
BlazerYost Bonnie
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.1007.22
Subject(s) - trpv4 , chemistry , transient receptor potential channel , choroid plexus , ion transporter , biophysics , paracellular transport , ion channel , microbiology and biotechnology , transepithelial potential difference , agonist , ussing chamber , endocrinology , medicine , receptor , biology , biochemistry , secretion , membrane , permeability (electromagnetism) , central nervous system
The Choroid Plexus (CP), which is responsible for the production of cerebrospinal fluid (CSF), is found in the lateral, third, and fourth ventricles of the brain. The CP is composed of a high resistance epithelium which surrounds a network of capillaries. The primary function of the barrier epithelium is regulated transport of ions and water that controls the production and movement of CSF. Transient Receptor Potential Vanilloid‐4 (TRPV4) is a calcium‐permeable ion channel on the apical membrane of the CP epithelium that is activated by a wide variety of stimuli including hypotonicity, fluid sheer stress and arachidonic acid metabolites. Our laboratory has shown that treatment with a TRPV4 antagonist inhibits hydrocephalus in a rat model of the disease. When TRPV4 is activated, the channel allows Ca 2+ to flow into the cells. The resulting increase in intracellular Ca 2+ can activate Ca 2+ ‐activated channels. The current study was designed to identify the channels secondarily activated in response to stimulation of TRPV4. A recently described high resistance porcine choroid plexus cell line (PCP‐R) was used to determine the effect of activation of TRPV4 with a specific channel agonist, GSK1016790A. Ussing chamber electrophysiology was used to monitor the transepithelial ion flux and transepithelial electrical resistance changes. Based on the direction of the ion flux stimulated in response to the agonist, it is likely that activation of TRPV4 mediates the secretion of a cation. One of the most likely families of cation channels are the Ca 2+ ‐activated K + channels. Neither the intermediate conductance potassium (IK, SK4) channel inhibitor TRAM34 nor the big potassium (BK) channel inhibitor iberiotoxin blocked the agonist‐stimulated transport. However, fluoxetine which inhibits the small conductance Ca 2+ ‐activated K + channels (SK1, SK2 and SK3), blocked TRPV4‐mediated transepithelial ion flux. The SK2‐specific inhibitor Tamapin, a potent scorpion toxin, was ineffective in blocking the TRPV4‐mediated transepithelial transport. These data suggest that the TRPV4 stimulated transepithelial ion flux involves either SK1 or SK3. TRPV4 activity may play a role in the homeostatic regulation of the composition of the CSF and the current data suggest that both TRPV4 and SK channels may be targets for the treatment of hydrocephalus. Support or Funding Information Hydrocephalus Association Innovator Award; Indiana University Collaborative Research Grant and Indiana Clinical and Translational Sciences Institute CTR Award.