The voltage-gated K+ channel subunit Kv1.1 links kidney and brain

Abstract

Analysis of Mendelian Mg2+ wasting disorders helps us to unravel the mechanisms of Mg2+ homeostasis. In this issue of the JCI, Glaudemans andcolleagues show that mutations in voltage-gated K+ channel subtype 1.1(Kv1.1) cause autosomal dominant hypomagnesemia in humans (see the related article beginning on page 936). Interestingly, other mutations in the same protein cause the neurological disease episodic ataxia type 1. The authors show, using cells with heterologous expression of the wild-type and mutant channels, that the mutant channel is dysfunctional and speculate that Mg2+ wasting results from changes in apical membrane voltage along the nephron. Mechanisms by which the apical voltage is generated and howKv1.1 fits within this context are discussed herein.

Figure 1. Schematic diagram of the anatomy, molecular pathways, and electrophysiology of Mg²⁺ transport along the distal nephron.

Top panel: Nephron segmentation, including the TAL and the DCT subsegments DCT1 and DCT2. Note that the transition from DCT1 to DCT2 is gradual. Middle panel: Transport pathways in these segments include Na⁺/K⁺-ATPase (~), the furosemide-sensitive Na⁺K⁺2Cl cotransporter (NKCC2), the Cl^– channel (CLCNKB), the epithelial Na⁺ channel (ENaC), and the thiazide-sensitive NaCl cotransporter (NCC). Mg²⁺ transport along the TAL is primarily paracellular. Along the DCT, however, it is mediated by TRPM6. Two K⁺ channels are present in the apical membrane: ROMK and, as shown by Glaudemans et al. in this issue of the JCI (5), Kv1.1 (see text for further details). K⁺ and Cl^– can exit DCT cells via a coupled K⁺/Cl^– cotransporter (KCC4) or a discrete K⁺ channel. Lower panel: Membrane voltages along each segment, in millivolts (mV). The basolateral voltage is similar in each cell type. V_TE, transepithelial voltage. As postulated by Glaudemans et al. (5), a defective Kv1.1 (indicated by red X) should depolarize the apical membrane (red bars) along the DCT, leading to hyperpolarization of the transepithelial voltage.