KCNJ18 Membrane Protein Introduction

Introduction of KCNJ18

Inward rectifier potassium channel 18 (KCNJ18), also known as K_ir2.6, is encoded by the KCNJ18 gene. It belongs to K_ir2 subfamily, inward-rectifier potassium channels (K_ir, IRK) family. The K_ir channels are activated by phosphatidylinositol 4,5-bisphosphate (PIP2) and contribute to the control of electrical activity in excitable tissues, the establishment of resting membrane potential, inhibition of neurotransmitter responses, regulation of nitric oxide synthase, decision of insulin release, etc. KCNJ18 is specifically expressed in skeletal muscle and is transcriptionally regulated by thyroid hormone. As other K_ir channels, KCNJ18 has two transmembrane domains, with a greater tendency for K⁺ uptake than K⁺ export, can stabilize the resting membrane potential near the potassium equilibrium potential, and tetramerize to form functional, inwardly rectifying channels. Significantly, the gene KCNJ18 contains a 5′-upstream thyroid hormone response element, which is essential for the transcriptional up-regulation of KCNJ18 by thyroid hormones.

Function of KCNJ18 Membrane Protein

The widely acknowledged function of KCNJ18 channel is the high pertinence with non-familial hypokalemic periodic paralysis (hypoKPP), consisting mainly of thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP). It was documented that mutations of KCNJ18 can affect membrane excitability of skeletal muscle, predisposing patients to muscle paralysis, and that thyroid hormones induced up-regulation of KCNJ18 is pivotal in the pathogenesis of TPP and SPP. The conserved heterozygous/heterozygous mutations in KCNJ18 gene result in V168M, R43C, and A200P amino acid substitution, which reduce the whole-cell currents down to 43%, 78%, nearly 0%, respectively. The decreased outward K⁺ current from hypofunction of KCNJ18 predisposes the sarcolemma to hypokalemia-induced paradoxical depolarization during attacks, which in turn leads to Na⁺ channel inactivation and inexcitability of muscles. Moreover, the patients with KCNJ18 mutation present shorter attack duration, higher prevalence of muscle soreness and weakness recurrence.

Fig.1 The role of Kir2.6 mutations in TPP pathophysiology. (Ryan, 2010)

Application of KCNJ18 Membrane Protein in Literature

1. Li X., et al. The clinical and genetic features in a cohort of mainland Chinese patients with thyrotoxic periodic paralysis. BMC Neurology. 2015, 15(1): 38. PubMed ID: 25885757
   
   

   In this article, the authors investigated 229 DNA samples from TPP patients and hyperthyroidism male controls and they demonstrated that the KCNJ18 variants were only responsible for a small proportion of TPP patients in mainland China, while the rs623011and rs312691 loci were significantly associated with TPP patients.

2. Cheng C.J., et al. Identification and functional characterization of K_ir2.6 mutations associated with non-familial hypokalemic periodic paralysis. Journal of Biological Chemistry. 2011, 5; 286(31): 27425-27435. PubMed ID: 21665951
   
   

   This article reported that V168M, R43C, and A200P amino acid substitution of K_ir2.6 in patients were associated with the pathogenesis of TPP/SPP. Compared with the wild type channel, whole-cell currents of R43C, V168M and A200P mutants were reduced by ~78, 43%, 0%, respectively.

3. Kuhn M., et al. Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients. J Neurol Neurosurg Psychiatry. 2016, 87(1): 49-52. PubMed ID: 25882930
   
   

   The authors sequenced KCNJ18 in 474 controls and 263 unrelated patients with periodic paralysis (PP), including 30 patients with TPP without mutations in established PP genes, then showed that many different, rare KCNJ18 alterations (c.-3G>A, L15S, R81C, E273X, T309I, I340T, N365S, G394R, R401W) were seldom pathogenic.

4. Paninka R.M., et al. Down-regulation of Kir2.6 channel by c-termini mutation D252N and its association with the susceptibility to Thyrotoxic Periodic Paralysis. Neuroscience. 2017, 346: 197-202. PubMed ID: 28131627
   
   

   This article revealed two heterozygous mutations: D252N and R386C in two TPP patients. D252N mutation was demonstrated to be responsible for the down-regulation of Kir2.6 activity, decrease of the K⁺ current density (~34%) and a substantial reduction of ~51% in membrane abundance when compared to the WT channel.

5. Ryan D.P., et al. Mutations in potassium channel K_ir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell. 2010, 140(1): 88-98. PubMed ID: 20074522
   
   

   This article firstly identified the KCNJ18 gene, a previously unreported gene, encoded an inwardly rectifying potassium (Kir) channel, Kir2.6. They showed that KCNJ18 was expressed in skeletal muscle and was transcriptionally regulated by thyroid hormone.

KCNJ18 Preparation Options

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Reference

1. Ryan D P, et al. (2010). Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell. 140(1): 88-98.

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