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KCNK3

Official Full Name
potassium channel, subfamily K, member 3
Background
This gene encodes a member of the superfamily of potassium channel proteins that contain two pore-forming P domains. The encoded protein is an outwardly rectifying channel that is sensitive to changes in extracellular pH and is inhibited by extracellular acidification. Also referred to as an acid-sensitive potassium channel, it is activated by the anesthetics halothane and isoflurane. Although three transcripts are detected in northern blots, there is currently no sequence available to confirm transcript variants for this gene.
Synonyms
KCNK3; potassium channel, subfamily K, member 3; potassium channel subfamily K member 3; K2p3.1; TASK; TASK 1; cardiac potassium channel; two pore K(+) channel KT3.1; two P domain potassium channel; two pore potassium channel KT3.1; TWIK-related acid-sens

Recent Research

KCNK3 is also called Twik-related acid-sensitive K+ channel (TASK1). The KCNK3 gene encodes for an outward K+ channel characterized by the presence of 4 transmembrane domains and 2 pore domains per subunit and is a member of 2-pore- domain K+ channels (K2P). It shares several characteristics with the background K+ current, including minimal voltage sensitivity, extracellular pH sensitivity, resistance to classic K+ channel inhibitors, and insensitivity to cytoplasmic Ca2+. This gene subfamily isconstitutively active at physiological resting membrane potentials in excitable cells, including smooth muscle cells, and has been particularly linked to the human pulmonary circulation. KCNK3 is sensitive to a wide array of physiological and pharmacological mediators that affect their activity such as unsaturated fatty acids, extracellular pH, hypoxia, anaesthetics and intracellular signalling pathways. Recent studies show that modulation of KCNK3, either directly or indirectly by targeting its regulatory mechanisms, has the potential to control pulmonary arterial tone in humans.

KCNK3 is highly expressed in human atrial cardiac myocytes and adrenal glomerulosa cells. Up-regulation of KCNK3 was reported in patients with chronic atrial fibrillation. Moreover,loss-of-function mutations in KCNK3 were also found to be associated with atrial fibrillation.Human KCNK3 variants are associated with hypertension and high plasma aldosterone levels. In addition, knockout mice lacking KCNK3 ischaracterised by impaired carotid body chemoreceptor function.

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary condition leading to right-sided heart failure and ultimately death. PAH caused by a KCNK3 mutation is an autosomal-dominant disease with incomplete penetrance. Recently, the identification of loss-of-function mutations in KCNK3 in some patients with PAH has highlighted a novel dysfunctional pathway and a potential therapeutic target. In addition, it has been demonstrated that loss of function of KCNK3 is a hallmark of idiopathic and heritable PAH and experimental pulmonary hypertension.

KCNK3 antagonizes norepinephrine-induced membrane depolarization by promoting potassium efflux in brown adipocytes. This limits calcium influx through voltage-dependent calcium channels and dampens adrenergic signaling, thereby attenuating lipolysis and thermogenic respiration. Adipose-specific KCNK3 knockout mice display increased energy expenditure and are resistant to hypothermia and obesity. These findings uncover a critical K+-Ca2+-adrenergic signaling axis that actstodampen thermogenesis, maintain tissue homeostasis, and reveal an electrophysiological regulatory mechanism of adipocyte function.

References:

  1. Higasa K, et al. A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension. BMC Pulmonary Medicine, 2017, 17(1).
  2. Antigny F, et al. Potassium-Channel Subfamily K-Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension. Circulation, 2016, 8(3):247-248.
  3. Olschewski A, et al. TASK-1 (KCNK3) channels in the lung: from cell biology to clinical implications. European Respiratory Journal, 2017, 50(5):1700754.

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