Ankyrin-3 is a novel binding partner of the voltage-gated potassium channel Kv1.1 implicated in renal magnesium handling

Abstract

The voltage-gated potassium channel, Kv1.1, was recently identified as a causative gene in isolated dominant hypomagnesemia. The channel is situated in the distal convoluted tubule, where it participates in maintaining a favorable electrical gradient for driving magnesium ion into the cell through the transient receptor potential melastatin 6 channel. Pull-down experiments coupled to mass spectrometry using the carboxy-terminal domain of Kv1.1 as bait were used in mouse kidney lysates. Ankyrin-3 (ANK3) was identified as a binding partner of Kv1.1 and was enriched in isolated distal convoluted tubules as compared to whole kidney. Electrophysiology studies performed in HEK293 cells expressing Kv1.1 showed that ANK3 significantly inhibited Kv1.1-mediated currents (267 compared to 125 pA/pF) for control and ANK3, respectively. Finally, to evaluate a potential role of ANK3 in magnesium handling, the intrarenal abundance of ANK3 was measured in mice fed a low-, normal-, or high-magnesium diet for 10 days. Mice maintained on high dietary magnesium significantly doubled their fractional urinary excretion of magnesium, which coincided with a 1.8-fold increase in the renal expression of ANK3 compared to mice on a normal- or low-magnesium diet. Thus, our observations demonstrate a novel role for ANK3 in modulating the biophysical properties of Kv1.1. Such regulation appears to be particularly important in conditions of high dietary magnesium.

Genome-wide association analysis of cystatin-C kidney function in continental Africa

“…ANK3 has been shown to regulate KCNA1 channel activity in the function of dietary Mg (2+) levels hence regulating renal Mg (2+) reabsorption. 24 Consistent with our findings, previous studies have shown the ANK3 gene to be associated with the kidney. 25 In 2014, Fagerberg et al.…”

Construction and Validation of a 9-Gene Signature for Predicting Prognosis in Stage III Clear Cell Renal Cell Carcinoma

“…ANK3 is mainly expressed in tissues such as kidney and gut epithelium (44), and encodes ankyrin-G isoforms that anchor membrane protein complexes to the cytoskeleton (45). It was discovered that ANK3 is implicated in renal magnesium handling (46) and polycystic kidney disease (47). Deregulation of ANK3 expression has been observed in multiple human cancers, and, while it contributes to poor prognosis (48), its mechanism remains unknown (49).…”

Ankyrin G Expression Regulates Apical Delivery of the Epithelial Sodium Channel (ENaC)

“…Previous studies have suggested that AnkR and AnkG may be essential for basolateral sorting of the Na ϩ / K ϩ -ATPase and ammonium (RhBG) transporters, respectively (44,57). Work by San-Cristobal et al (58) has shown that AnkG inhibits current through the potassium channel Kv1.1, which establishes a favorable driving force for Mg 2ϩ entry into the distal tubules of mice.…”