KCND3

Official Full Name

potassium voltage-gated channel subfamily D member 3

Organism

Homo sapiens

GeneID

3752

Background

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene. [provided by RefSeq, Jul 2008]

Synonyms

KV4.3; SCA19; SCA22; BRGDA9; KCND3L; KCND3S; KSHIVB;

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Detailed Information

Recent Research

KCND3 encodes the voltage-gated potassium channel Kv4.3, a membrane protein that consists of six trans-membrane segments (S1-S6) and two intra- cellular tails. Four Kv4.3 subunits co-assemble to form the pore domain (helices S5-S6), the potassium selective conduction pathway. The S1-S4 segments form a single voltage-sensor domain that surrounds the pore domain, connected by the S4-S5 loop, and responds to changes in membrane voltages controlling the pore gates. Kv4.3 rapidly activates and inactivates in response to membrane depolarization, contributing to the neuronal subthreshold A-type potassium currents and controlling the action potential repolarization and frequency, and thus neuronal excitability. The channel characteristics of Kv4.3 including protein trafficking, channel expression and activity can be modified by Kv channel-interacting protein 2 (KChIP).

Kv4.3 is a Shal-related subfamily, involved in the transient outward A-type Kb current in the neurons, Kv4.3 channels are important molecular components of transient K+ currents (Ito currents) in brain and heart. It has been reported that mutations in KCND3 either impaired proper endoplasmic reticulum (ER)–Golgi membrane trafficking or reduced Kv4.3 channel functioning. Kv4.3 channels are involved in setting the frequency of neuronal firing and heart pacing. Altered Kv4.3 channel expression has been demonstrated under pathological conditions like heart failure indicating their critical role in heart function. Thyroid hormone studies suggest that their expression in the heart may be hormonally regulated. In addition, spinocerebellar ataxia type 19/22 (SCA19/22) is a dominantly inherited neurodegenerative, clinically heterogeneous disorder caused by mutations in KCND3. Currently, all the SCA19/22 mutations that have been reported lead to a loss of Kv4.3 current amplitude in studies focused on single mutant Kv4.3 subunits. Besides, multiple mutations in KCND3 have been reported to be associated with the pathogenesis of Brugada syndrome (BrS) and sudden unexplained death syndrome. Moreover, atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that results in serious cardiovascular outcomes such as stroke, heart failure and death. It has been identified a novel T361S missense mutation, which is connected with AF, in KCND3.The T361S mutant result in the changes in channel kinetics as well as the up-regulation of Kv4.3 protein.

References:

Yuan Huang, et al. A novel KCND3 mutation associated with early-onset lone atrial fibrillation. Oncotarget, 2017, 8(70):115503-115512.
Duarri A, et al. Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner. Cellular & Molecular Life Sciences Cmls, 2015, 72(17):3387-99.
Gonzalez W G, et al. Modulation of the Voltage-gated Potassium Channel (Kv4.3) and the Auxiliary Protein (KChIP3) Interactions by the Current Activator NS5806. Journal of Biological Chemistry, 2014, 289(46):32201-32213.
Smets K, et al. First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy. Bmc Medical Genetics, 2015, 16(1):51.

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