The voltage‐operated Potassium channel Kv1.1 as new player in renal Magnesium handling

Abstract

Genetic studies in families with hereditary forms of renal Mg2+ wasting revealed new genes involved in Mg2+ homeostasis such as Mg2+ channel TRPM6. Likewise, this study aims to find the affected gene in a Brazilian family with isolated dominant hypomagnesemia. SNP‐based linkage analysis was used to identify a 11.6 cM critical region on chromosome 12. We sequenced the KCNA1 gene and identified a heterozygous A763G mutation that co‐segregated with the disorder. KCNA1 encodes voltage‐gated K+ channel Kv.1.1 in which the mutation causes substitution of a conserved asparagine at position 255 for an aspartic acid (N255D). Kv.1.1 is expressed in kidney, where it co‐localizes with TRPM6 at the distal convoluted tubule (DCT) luminal membrane as shown by immunohistochemistry. Functional analysis showed that the N255D mutation results in a non‐functional channel with a dominant negative effect on the wild‐type channel. Next, we revealed that the N255D channel fails to hyperpolarize the cell membrane. The N255 residue was further characterized by substitution with six amino acids (E, Q, A, V, T, H). The Kv1.1 N255E and N255Q mutants were not functional, while the other mutants were similar to wild‐type. Yet, their channel kinetics significantly changed, suggesting a role for Kv1.1 N255 in channel gating. Kv1.1 likely establishes the membrane potential across the DCT luminal membrane to drive TRPM6‐mediated Mg2+ reabsorption.