AUTHOR=Christensen Henriette L., Nguyen An T., Pedersen Fredrik D., Damkier Helle H.

TITLE=Na+ dependent acid-base transporters in the choroid plexus; insights from slc4 and slc9 gene deletion studies

JOURNAL=Frontiers in Physiology

VOLUME=4

YEAR=2013

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2013.00304

DOI=10.3389/fphys.2013.00304

ISSN=1664-042X

ABSTRACT=<p>The choroid plexus epithelium (CPE) is located in the ventricular system of the brain, where it secretes the majority of the cerebrospinal fluid (CSF) that fills the ventricular system and surrounds the central nervous system. The CPE is a highly vascularized single layer of cuboidal cells with an unsurpassed transepithelial water and solute transport rate. Several members of the <italic>slc4a</italic> family of bicarbonate transporters are expressed in the CPE. In the basolateral membrane the electroneutral Na<sup>+</sup> dependent Cl<sup>−</sup>/HCO<sub>3</sub><sup>−</sup> exchanger, NCBE (<italic>slc4a10</italic>) is expressed. In the luminal membrane, the electrogenic Na<sup>+</sup>:HCO<sub>3</sub><sup>−</sup> cotransporter, NBCe2 <italic>(slc4a5)</italic> is expressed. The electroneutral Na<sup>+</sup>:HCO<sub>3</sub><sup>−</sup> cotransporter, NBCn1 (<italic>slc4a7</italic>), has been located in both membranes. In addition to the bicarbonate transporters, the Na<sup>+</sup>/H<sup>+</sup> exchanger, NHE1 (<italic>slc9a1</italic>), is located in the luminal membrane of the CPE. Genetically modified mice targeting <italic>slc4a2</italic>, <italic>slc4a5</italic>, <italic>slc4a7</italic>, <italic>slc4a10</italic>, and <italic>slc9a1</italic> have been generated. Deletion of <italic>slc4a5, 7</italic> or <italic>10</italic>, or <italic>slc9a1</italic> has numerous impacts on CP function and structure in these mice. Removal of the transporters affects brain ventricle size (<italic>slc4a5</italic> and <italic>slc4a10</italic>) and intracellular pH regulation (<italic>slc4a7</italic> and <italic>slc4a10</italic>). In some instances, removal of the proteins from the CPE (<italic>slc4a5, 7</italic>, and <italic>10</italic>) causes changes in abundance and localization of non-target transporters known to be involved in pH regulation and CSF secretion. The focus of this review is to combine the insights gathered from these knockout mice to highlight the impact of <italic>slc4</italic> gene deletion on the CSF production and intracellular pH regulation resulting from the deletion of <italic>slc4a5, 7</italic> and <italic>10</italic>, and <italic>slc9a1</italic>. Furthermore, the review contains a comparison of the described human mutations of these genes to the findings in the knockout studies. Finally, the future perspective of utilizing these proteins as potential targets for the treatment of CSF disorders will be discussed.</p>