KCNQ2

Official Full Name

potassium voltage-gated channel subfamily Q member 2

Organism

Homo sapiens

GeneID

3785

Background

The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

EBN; BFNC; DEE7; EBN1; ENB1; HNSPC; KV7.2; KCNA11;

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Detailed Information

Recent Research

KCNQ encodes for the voltage-dependent potassium (K⁺) channels. KCNQ channels play a critical role in maintaining neuronal excitability and have emerged as a potential target for the treatment and prevention of epilepsy and other related disorders, including neuropathic pain and tinnitus.

KCNQ channels are composed of five subunits (KCNQ1-5): KCNQ2-5 are confined to the nervous system including inner ear and brainstem whereas KCNQ1 is limited to the heart and peripheral epithelial and smooth muscle cells. KCNQ2 and KCNQ3 channels were activated at the subthreshold potential generation of action potential. Thus, they allow the excitation of single action potential but effectively inhibit the repeated excitation of action potential. Originally named ‘‘M- channels’’, their inhibition by muscarinic agonists profoundly increases action potential firing. In vivo, overexpression of KCNQ2 dominant negative subunit in transgenic mice significantly reduced M current, resulting in increased excitability and seizures. This dominant-negative subunit hybridizes with the KCNQ3 subunit to eliminate all functions of KCNQ2/3. Moreover, pathological reduction in KCNQ2/3 channel activity is involved in different classes of seizures, anxiety, migraine, attention deficient-hyperactivity disorder, neuropathic pain, schizophrenia, mania and bipolar disease.

In neuronal cells, KCNQ2 heterotetramerizes to give rise to the M current (I_M), two key players for the regulation of neuronal excitability. Recently, KCNQ2 mutations had only been reported in benign familial neonatal epilepsy (BFNE) and peripheral nerve hyperexcitability or myokymia. Patients with BFNE may experience severe local movement spasms in the first few days of life, normal or subnormal interictal EEG activity and usually normal cognitive development. The epilepsy usually stops before the end of the 3rd month. In BFNE, KCNQ2 mutations are transmitted from affected individual to affected individual following a classical autosomal dominant inheritance mode. More recently, mutations in the KCNQ2 gene were also described in a very severe epileptic phenotype called early infantile epileptic encephalopathy (EIEE) subtype. Contrary to what is observed in BFNE, the patients present a severe phenotype with most often a suppression burst EEG pattern and frequent polymorphic seizures. In most cases, the evolution is poor with severe neurological impairment accompanied by severe intellectual deficiency. Furthermore, a proportion of patients die within the first years of life. Mutations causing EIEE had occurred de novo in most cases.

In addition, KCNQ2 channel and voltage-gated sodium channels (VGSCs) are enriched in the axon initial segment (AIS) where they bind to ankyrin-G and coregulate membrane potential in central nervous system neurons. It has been shown that fibroblast growth factor 14 (FGF14), described as a VGSC regulator affects KCNQ function and localization. FGF14 knockdown leads to a reduction of KCNQ2 in the AIS and a reduction in whole-cell KCNQ currents. FGF14 positively regulates KCNQ2 channel in a simplified expression system. FGF14 interacts with KCNQ2 at a site distinct from the FGF14–VGSC interaction surface, thus enabling the bridging of Na_V1.6 and KCNQ2.

References:

Kalappa B I, et al. Potent KCNQ2/3-Specific Channel Activator Suppresses In Vivo Epileptic Activity and Prevents the Development of Tinnitus. Journal of Neuroscience, 2015, 35(23):8829-8842.
Soh H, et al. Conditional Deletions of Epilepsy-Associated KCNQ2 and KCNQ3 Channels from Cerebral Cortex Cause Differential Effects on Neuronal Excitability. Journal of Neuroscience, 2014, 34(15):5311-5321.
Milh M, et al. Variable clinical expression in patients with mosaicism for KCNQ2 mutations. American Journal of Medical Genetics Part A, 2015, 167(10):2314-2318.

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