KCNT1 Membrane Protein Introduction

Introduction of KCNT1

KCNT1, potassium channel subfamily T member 1 is a protein that in humans is encoded by the KCNT1 gene. It is also called K_Ca4.1. K_Ca4.1 is a member of the calcium-activated potassium channel protein family. It can be activated by high intracellular sodium or chloride levels. It can also be activated upon stimulation of G-protein coupled receptors, such as CHRM1 and GRIA1. Mutations in the KCNT1 gene have been shown to be a cause of Early Infantile Epileptic Encephalopathy.

Function of KCNT1 Membrane Protein

KCNT1 belongs to the potassium channel, which is also called K_Ca4.1 - calcium-activated potassium channel. It’s biased expressed in the brain, spleen, and other 2 tissues. The structure and function of potassium channels are both complicated. The various functions are mainly focused on regulating neurotransmitter release, insulin secretion, heart rate, epithelial electrolyte transport, neuronal excitability, cell volume and smooth muscle contraction. KCNT1 plays a functional role in ion conductance and signaling pathway development. It can be activated not only by high intracellular sodium or chloride levels, but also upon stimulation of G-protein coupled receptors, such as CHRM1 and GRIA1. It may be regulated by calcium in the absence of sodium ions (in vitro). Mutations in the KCNT1 gene have been shown to be a cause of Early Infantile Epileptic Encephalopathy, early-onset epileptic disorders, autosomal dominant nocturnal frontal lobe epilepsy, and malignant migrating mechanisms.

Fig.1 Schematic diagram of the location of mutations in KCNT1. (McTague, 2018)

Application of KCNT1 Membrane Protein in Literature

1. Niday Z and Tzingounis A.V. Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox. Neuroscientist. 2018, 24(4):368-380. PubMed ID: 29542386
   
   

   This article describes the current state of the identified gain-of-function potassium channel variants with epilepsy including KCNT1. The authors figure out the mechanism of potassium channel gain-of-function leads to epilepsy, providing new insights into the inner working of neural circuits and aid in developing new therapies.

2. McTague A., et al. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology. 2018, 90(1):e55-e66. PubMed ID: 29196579
   
   

   This article characterizes the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy and shows that KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy.

3. Mullen S.A., et al. Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine. Neurology. 2018, 90(1):e67-e72. PubMed ID: 29196578
   
   

   This study evaluates quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1.

4. Mikati M.A., et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol. 2015, 78(6):995-9. PubMed ID: 26369628
   
   

   This article reveals that the epilepsy patient with KCNT1 mutations has drug-resistant treated with quinidine. This suggests caution in quinidine’s application for KCNT1 mutated epilepsy.

5. Milligan C.J., et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol. 2014, 75(4):581-90. PubMed ID: 24591078
   
   

   This article demonstrates that KCNT1 mutations implicated in epilepsy cause a marked increase in function and treatment with quinidine significantly reduces this gain of function for all mutations studied.

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Reference

1. McTague A, et al. (2018). Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology. 90(1):e55-e66.

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