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Pathological mutation L241P in Kir7.1 channel inhibits its activity in the choroid plexus epithelium and decreases cerebrospinal fluid K+ concentration in the mouse
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DOI：10.1007/s13105-026-01220-z.png)
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Abstract
En 中文
The inwardly rectifying K+ channel Kir7.1 is prominently expressed at the apical membrane of the choroid plexus epithelium (CPE) and defines the membrane potential of these cells. The unusual independence of its conductance of extracellular K+ ([K+]o) underpins an important role in the regulation of the concentration of this ion in the cerebrospinal fluid [K+]CSF. A similar function for retinal pigment epithelium (RPE) Kir7.1 has been proposed with respect to subretinal K+ ([K+]SRS) buffering. We have now studied the effect of expressing in mice the mutant Kir7.1-L241P, a blindness-associated Leber’s congenital amaurosis mutation, on channel expression and function in the CPE and on [K+]CSF, taken as a proxy for less accessible [K+]SRS. We used genome-edited knockin mice carrying the L241P mutation of Kir7.1 and studied the electrical properties and NKCC1 cotransporter activity of CPE cells in vitro, as well as CSF secretion rate and [K+]CSF in vivo. CPE cells from Kir7.1-L241P knockin mice had a two-third reduction in K+ conductance with respect to that of cells from control animals. While CSF secretion rates and NKCC1 cotransporter activity were unaltered in mutant animals, [K+]CSF was significantly decreased while [Na+]CSF is increased. These results reaffirm the importance of choroid plexus Kir7.1 in the regulation of [K+]CSF. We speculate that the alteration in [K+]CSF regulation by mutation Kir7.1-L241P might be paralleled by a disease-related impairment of retinal [K+]SRS buffering. The choroid plexus (CPE) and retinal pigment (RPE) epithelia respectively flank the cerebrospinal and subretinal space fluids. CPE and RPE are the sites of highest expression of Kir7.1 K+ channels in mammals, and from these locations K+ concentration is regulated in the cerebrospinal and subretinal space fluids respectively. Genome-edited mice carrying the blindness-associated Kir7.1-L241P mutant showed decreased channel function in the CPE and disturbed regulation of K+ in the cerebrospinal fluid. A similar failure in the regulation of retinal K+ concentration may be associated with the blindness phenotype.
Keywords:
Cerebrospinal fluid ion concentration
Cerebrospinal fluid secretion
Choroid plexus epithelium
Kir7.1
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