Role of Kir7.1 K ⁺ channel in retinal pigment epithelium probed in a Kir7.1-M125R-expressing mutant mouse

Eye disease-associated K + channel Kir7.1 is highly expressed together with the Na + -K + pump at the apical membrane of retinal pigment epithelial cells (RPE) which line the subretinal space (SRS). SRS K + concentration ([K + ] SRS ) decreases from ~5 to 2 mM upon light stimulation. Kir7.1 is crucial in its buffering, with failure thought to be causal in visual disease mutations of its gene. The unusual inverse relation to [K + ] o of its conductance, deemed essential for [K + ] SRS buffering, relies on non-conserved outer pore methionine-125. We now probe the role of Kir7.1 in the visual process by generating Kir7.1-M125R mutant mice with the channel predicted to lack [K + ] SRS buffering ability. RPE cell electrical properties and mouse electroretinograms (ERG) are assessed. Membrane potential of RPE cells was found to be dominated by K + , but while conductance decreased with increasing [K + ] o in control cells, the reverse was true for cells of Kir7.1-M125R-expressing mice. ERG of mutant animals revealed a larger c-wave than in controls, consistent with the relative K + permeabilities of the RPE. In contrast, there was no difference between the a- and b-waves of Kir7.1-M125R and control mice, suggesting normal functioning of photoreceptors and bipolar cells, and therefore retinal processing of the light signal. If, as predicted, [K + ] SRS buffering is altered in mutant animals, this does not affect the retinal processing of the light signal. Other consequences of Kir7.1 malfunction, such as proposed function in photoreceptor outer segment recycling, must be involved in originating the disease phenotype associated with mutations in its gene.