Kir5.1 channels: potential role in epilepsy and seizure disorders

Abstract

Inwardly rectifying potassium (Kir) channels are broadly expressed in many mammalian organ systems, where they contribute to critical physiological functions. However, the importance and function of the Kir5.1 channel (encoded by the KCNJ16 gene) have not been fully recognized. This review focuses on the recent advances in understanding the expression patterns and functional roles of Kir5.1 channels in fundamental physiological systems vital to potassium homeostasis and neurological disorders. Recent studies have described the role of Kir5.1-forming Kir channels in mouse and rat lines with mutations in the Kcnj16 gene. The animal research reveals distinct renal and neurological phenotypes, including pH and electrolyte imbalances, blunted ventilatory responses to hypercapnia/hypoxia, and seizure disorders. Furthermore, it was confirmed that these phenotypes are reminiscent of those in patient cohorts in which mutations in the KCNJ16 gene have also been identified, further suggesting a critical role for Kir5.1 channels in homeostatic/neural systems health and disease. Future studies that focus on the many functional roles of these channels, expanded genetic screening in human patients, and the development of selective small-molecule inhibitors for Kir5.1 channels, will continue to increase our understanding of this unique Kir channel family member.

Keywords: SIDS; deafness; kcnj10; kcnj16.

Graphical abstract

Figure 1.

Inwardly rectifying potassium Kir5.1 (KCNJ16) expression and function in the brain. Despite the recently accumulated evidence about the role of Kir5.1 in several pathologies, the knowledge about the expression, functional heteromerization, and physiological function is largely unresolved.

Figure 2.

Bulk brain tissue gene expression for KCNJ16. The transcripts per million (TPM) values are generated from the Genotype-Tissue Expression (GTEx) mapping of KCNJ16 expression in the human brain (sample size for female and male groups are reflected in the x-axis) (https://www.gtexportal.org/home/gene/KCNJ16).

Figure 3.

The expression of inwardly rectifying potassium (Kir)5.1 subunit in the cochlea lateral wall. The circulation of K⁺ in cochlear endolymph is essential for hair cells function. K⁺ is transported to the spiral ligament of the cochlear wall, a connective tissue comprising several types of fibrocytes, and recycled through the basal cells of stria vascularis. Kir5.1 is specifically expressed in type II, IV, and V fibrocytes of the spiral ligament. In contrast, Kir4.1 expression is limited to either type I or III fibrocytes. Created with BioRender.com.

Figure 4.

Family pedigrees and localization of identified variants in KCNJ16. A: pedigrees of seven families with eight affected individuals and homozygous or compound heterozygous variants in KCNJ16. Parental consanguinity is indicated by double bars in families A and G. Compound heterozygosity for KCNJ16 variants was analyzed by segregation analysis in the parents. B: localization of variants p.T64I, p.I132R, p.G135A, p.R137C, p.R176*, and p.P250L in the inwardly rectifying potassium (Kir)5.1 channel. Missense variants p.I132R, p.G135A, and p.R137C are located in the pore-forming domain near the selectivity filter of the ion channel. p.T64I is located in the N-terminus near the first transmembrane domain, p.R176* and p.P250L are located in the C-terminus. Adapted from Ref. with permission. C: the identified Kir5.1 mutations are located in highly conserved residues between the species (rodent and human comparisons are shown) and between different evolution groups of Kir channels. Amino acids and corresponding sequence number indicated (Q9NPI9 human isoform, UniProtKB). Red shows mutated human variants represented at B.

Figure 5.

Effects of dietary supplementation on mortality and blood pressure in Dahl salt-sensitive rats with Kcnj16 knockout (SS^{Kcnj16−/−}) rats. A: the survival rate of Dahl salt-sensitive (SS) and SS^{Kcnj16−/−} rats on a 4% NaCl diet. High-salt intake triggers rapid mortality of SS^{Kcnj16−/−} rats. B: the combination of a high-potassium diet and Kir5.1 channel deletion mediate the protective effects on the development of SS hypertension. Shown is the summary of mean arterial pressure (MAP) in SS and SS^{Kcnj16−/−} rats. Animals were switched from a 0.4% to a 4% NaCl diet at day 0. Then, SS rats were fed either a standard 4% NaCl diet (black) or a 4% NaCl diet supplemented with high K⁺ (2% KCl; green). SS^{Kcnj16−/−} rats were fed a 4% diet supplemented with high K⁺ (red). Adapted from Ref. with permission.

Figure 6.

Ventilatory CO₂/pH sensitivity is reduced in Dahl salt-sensitive rats with Kcnj16 knockout (SS^{Kcnj16−/−}) rats. Individual data and best-fit plots for the relationship between arterial pH (A) or $\text{P}{\text{a}}_{\text{C}{\text{O}}_2}$ (B) and ventilation during room air breathing or 3%, 5%, or 7% inspired CO₂ in SS controls (blue) and SS^{Kcnj16−/−} rats (gray). C: mean data for the slope of the ventilatory responses from individual animals presented in (A) and (B). Adapted from Ref. with permission.

Figure 7.

Dahl salt-sensitive rats with Kcnj16 knockout (SS^{Kcnj16−/−}) rats exhibit audiogenic seizures. A: latency from the start of the acoustic stimulus (10 kHz) to each behavioral stage in seizures that were given a score of 3. B: Kaplan–Meier survival analysis of SS^WT and SS^{Kcnj16−/−} rats during once daily exposure to the 10 kHz acoustic tone. C: summary of seizure severity scores in response to acoustic stimuli (0.1, 1, and 10 kHz; 2 min each) in male SS^WT and SS^{Kcnj16−/−} rats. D: average seizure severity (scores averaged over the 10 days for each animal) of SS^{Kcnj16−/−} rats during the 10× protocol is compared between rats fed a normal-K⁺ diet (NKD, 0.36% K⁺) vs. a high-K⁺ diet (HKD, 1.41% K⁺). E: graphical abstract summarizing audiogenic seizures in SS^{Kcnj16−/−} rats. Adapted from Ref. with permission.