KCNQ3 Membrane Protein Introduction

Introduction of KCNQ3

KCNQ3 is encoded by the KCNQ3 gene which is located on 8q24 in human. The molecular mass of KCNQ3 is about 96 kDa. It belongs to the wildly-expressed potassium channel family. KCNQ3 is mainly expressed in the brain. Just like KCNQ2, KCNQ3 can also be ubiquitinated by NEDD4L, an E3 ligase. And it has also been found that KCNQ3 can be phosphorylated.

Function of KCNQ3 Membrane Protein

KCNQ3 combines with KCNQ2 or KCNQ5 to form a potassium channel. KCNQ3 also takes part in chemical synaptic transmission, membrane hyperpolarization, calmodulin binding and many other biological processes. It has been proved that the mutations of KCNQ3 are associated with seizures, benign familial neonatal 2 (BFNS2), which is a disorder characterized by clusters of seizures occurring at the beginning of life. Besides, the expression of KCNQ3 also contributes to the etiology of bipolar disorder (BPD), and DNA methylation of KCNQ3 may be important in the etiopathogenesis of BPD. Accordingly, phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane can influence the KCNQ channels, including KCNQ3. And PIP2 can interact with four different domains synergistically to alter the activity of KCNQ3, including the A-B helix linker, the junction between S6 and the A helix, the S4-S5 linker and the S2-S3 linker. Beyond that, KCNQ3 and KCNQ2 also play central roles in regulating pyramidal neuron excitability and spiking behavior.

Fig.1 KCNQ topology. VSD voltage-sensing domain. (Manville, 2018)

Application of KCNQ3 Membrane Protein in Literature

1. Manville R.W. and Abbott G.W. Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket. Nat Commun. 2018, 9(1):3845. PubMed ID: 30242262
   
   

   It has been revealed that KCNQ3 and KCNQ2 can form heteromer, underlying the neuronal M-current, which suppresses neuronal excitability to protect against seizures. This article develops the new anticonvulsants by achieving similar KCNQ2/3 opening and increases the maximal effect.

2. Choveau F.S., et al. Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates KCNQ3 K⁺, channels by interacting with four cytoplasmic channel domains. Journal of Biological Chemistry. 2018, 293. PubMed ID: 30348901
   
   

   Accordingly, KCNQ3 can regulate the KCNQ3 K⁺ channel, but the mechanism is not very clear. So, the authors in this article find four cytoplasmic channel domains that PIP2 will interact with, they are the A-B helix linker, the junction between S6 and the A helix, the S4-S5 linker and the S2-S3 linker.

3. Miceli F., et al. A novel KCNQ3, mutation in familial epilepsy with focal seizures and intellectual disability. Epilepsia. 2015, 56(2): e15-e20. PubMed ID: 25524373
   
   

   This article reports a novel mutation in KCNQ3 from a family in which early onset epilepsy and neurocognitive deficits. It reveals that KCNQ3 can also be found in patients with more severe phenotypes including intellectual disability, just like KCNQ2.

4. Soldovieri M.V., et al. Novel KCNQ2 and KCNQ3 Mutations in a Large Cohort of Families with Benign Neonatal Epilepsy: First Evidence for an Altered Channel Regulation by Syntaxin-1A. Human Mutation. 2014, 35(3):356-367. PubMed ID: 24375629
   
   

   Mutations in the KCNQ3 gene cause neonatal epilepsies with wide phenotypic heterogeneity. Authors in this article describe clinical, genetic, and functional data from 17 patients/families. One substitution is found in KCNQ3.

5. Manville R.W. and Geoffrey A. Gabapentin is a potent activator of KCNQ3 and KCNQ5 potassium channels. Molecular Pharmacology. 2018, 118.112953. PubMed ID: 30021858
   
   

   Synthetic gabapentinoids are wildly used in several indications including epilepsy, neuropathic pain, anxiety, and alcohol withdrawal. And authors in this article reveal that gabapentin may be an activator of KCNQ3.

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Reference

1. Manville R W and Abbott G W. (2018). Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket. Nature communications. 9(1): 3845.

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