KCNC4

Official Full Name

potassium voltage-gated channel subfamily C member 4

Organism

Homo sapiens

GeneID

3749

Background

The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and is comprised of four subfamilies. Based on sequence similarity, this gene is similar to the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes. It generates atypical voltage-dependent transient current that may be important for neuronal excitability. Multiple transcript variants have been found for this gene. [provided by RefSeq, Jul 2010]

Synonyms

KV3.4; C1orf30; KSHIIIC; HKSHIIIC;

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Detailed Information

Recent Research

Kcnc4, also known as Kv3.4, are expressed in muscle, mossy fiber neurons, Purkinje neurons, spinal cord, and dorsal root ganglia (DRG). The DRG is a heterogeneous tissue, including neurons with small-diameter somas that are likely to be nociceptors. Neuropathic chronic pain resulting from hyperexcitable of peripheral nociceptors often implicates maladaptive up-regulation of voltage-gated Na⁺ (Nav) channels and down-regulation of voltage-gated K⁺ (Kv) channels in small-diameter nociceptors. Kv3.4 is one of the Kv channels in nociceptors, which is down-regulated in both nerve injury and bone cancer pain models. Some reports showed that fast-inactivating Kv3.4 channels are expressed at high levels in small-diameter DRG neurons and confirmed that they undergo dramatic modulation of N-type inactivation by protein kinase C (PKC) in a native environment. Under normal conditions, this modulation mainly regulates action potential (AP) duration and repolarization rate, and thus could drive a homeostatic response that is lost in the chronic pain state.

Voltage-gated potassium (Kv) channels are transmembrane channels that are specific to potassium and sensitive to voltage changes in numerous cells. In neuronal cells, Kv currents play important roles in regulating numerous neurophysiological functions, including resting membrane potential, spontaneous firing rate, and apoptosis. Among the Kv3 subfamily, Kv3.4 is oxygen-sensitive channel, which also known as oxidation-sensitive channel. The channel is characterized by fast voltage-dependent inactivation; the cytoplasmic N-terminus has a positively charged ball that provokes the fast closing of the channel by occluding the pore once it is opened. Oxidation of a cysteine residue in the amino terminus of the channel interrupts its fast inactivation by forming a disulfide bond and consequently increasing current amplitude; Kv3.4 loses its fast inactivation upon the external application of H₂O₂. In the rabbit carotid body, Kv3.4 participates in the chronic hypoxia sensitization of carotid body chemoreceptor cells as an oxygen-sensitive channel; Kv3.4 expression is down-regulated and Kv3.4 current is diminished under hypoxic conditions.

Kv3.4 is well documented as a potential therapeutic target for Alzheimer’s disease. Kv3.4 is over-expressed in both the early and advanced stages of this neurodegenerative disease, and the up-regulation of Kv3.4 leads to altered electrical and synaptic activity. Kv3.4 and its accessory protein MinK-Related Peptide 2 (MIRP2) are involved in neuronal cell death induced by neurotoxic amyloid β-peptide, which is generated from amyloid precursor protein and whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer’s disease patients. The oxidation-sensitive channel Kv3.4 likely plays a pivotal role in neuronal cell death induced by oxidative stress because oxidative stress is generated from amyloid β-peptide-associated ROS. Furthermore, oxidative stress is one of the general premonitory symptoms of neurodegenerative diseases.

References:

Song MS, et al. Kv3.4 is modulated by HIF-1α to protect SH-SY5Y cells against oxidative stress-induced neural cell death. Sci Rep, 2017, 7(1).
Ritter D M, et al. Dysregulation of Kv3.4 Channels in Dorsal Root Ganglia Following Spinal Cord Injury. Journal of Neuroscience the Official Journal of the Society for Neuroscience, 2015, 35(3):1260.
Ritter D M, et al. Kv3.4 channel function and dysfunction in nociceptors. Channels, 2015, 9(4):209-217.

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