Disease relevance of KCNE3

• This localization and the pharmacology, voltage-dependence and stimulation by cyclic AMP of KCNQ1/KCNE3 currents indicate that these proteins may assemble to form the potassium channel that is important for cyclic AMP-stimulated intestinal chloride secretion and that is involved in secretory diarrhoea and cystic fibrosis [1].
• Ménière's disease is associated with single nucleotide polymorphisms in the human potassium channel genes, KCNE1 and KCNE3 [2].
• A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis [3].
• On the other hand, we were able to identify the R83H mutation in the KCNE3 gene in one sporadic case of THypoKPP, a man who had been asymptomatic until developing thyrotoxicosis caused by Graves' disease; we confirmed the disease-causing mutation in 2 of 3 descendants [3].
• [KCNE3 R53H substitution in familial atrial fibrillation.] [4].

High impact information on KCNE3

• The subthreshold, voltage-gated potassium channel of skeletal muscle is shown to contain MinK-related peptide 2 (MiRP2) and the pore-forming subunit Kv3 [5].
• A missense mutation is identified in the gene for MiRP2 (KCNE3) in two families with periodic paralysis and found to segregate with the disease [5].
• Thus, MiRP2-Kv3.4 channels set resting membrane potential (RMP) and do not produce afterhyperpolarization or cumulative inactivation to limit action potential frequency [5].
• An aliphatic amino acid substituted at position 58 of minK is capable of reproducing KCNE3-like kinetics and voltage-independent constitutive current activation [6].
• An intermediate phenotype produced by several smaller aliphatic-substituted mutants yields conditional voltage independence that is distinct from the voltage-dependent gating process, suggesting that KCNE3 traps the channel in a stable open state [6].

Chemical compound and disease context of KCNE3

• Inherited mutation of aspartate to asparagine (D --> N) to yield D76N-MinK is linked to cardiac arrhythmia and deafness; the analogs D82N-MiRP1 and D90N-MiRP2 were studied [7].

Biological context of KCNE3

• Regulatory subunit KCNE3 (E3) interacts with KCNQ1 (Q1) in epithelia, regulating its activation kinetics and augmenting current density [8].
• The SNPs analyses identified 112G/A SNP in the KCNE1 gene and 198T/C SNP in the KCNE3 gene in 63 definite MD cases as well as 205 and 237 non-MD control subjects [2].
• Inhibition of hKCNE1- and hKCNE3-containing channels was weaker with IC50 values of 370 and 440 nM, respectively [9].
• Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis [10].
• An R83H point mutation in KCNE3-encoded MiRP2 has been reported to cause 2% of all cases of familial periodic paralysis [11].

Anatomical context of KCNE3

• Western blotting showed KCNE3 expression in a plasma membrane-enriched fraction from rat hepatocytes [12].
• (4) Using apically permeabilised epithelia it was shown that 7,8-benzoquinoline activates an intermediate-conductance calcium-sensitive potassium channel (KCNN4) and a cAMP-sensitive potassium channel (KCNQ1/KCNE3) in the basolateral epithelial membranes [13].
• In the colon and small intestine, KCNQ1 is coassembled with KCNE3 to play an important role in transepithelial cAMP-stimulated Cl- secretion [14].
• Thus, MiRP2 operates with a classical potassium channel subunit to govern skeletal muscle function and pathophysiology [5].
• 1. Altering native MiRP2 expression levels by RNAi gene silencing or cDNA transfection toggles the magnitude and kinetics of endogenous delayed rectifier currents in PC12 cells and hippocampal neurons [15].

Associations of KCNE3 with chemical compounds

• KCNQ1 can also co-assemble with KCNE3, and may be the molecular correlate of the cyclic AMP-regulated K(+) current present in colonic crypt cells [16].
• Secramine B interfered with a cAMP-gated and Ba2+-sensitive K+ channel, presumably KCNQ1/KCNE3 [17].
• 4. Here we show that MiRP2 has a single, functional PKC phosphorylation site at serine 82 and that normal MiRP2-Kv3.4 function requires phosphorylation of the site [10].
• Mutation of arginine to histidine (R --> H) to yield R83H-MiRP2 is associated with periodic paralysis; the analogs K69H-MinK and K75H-MiRP1 were also studied [7].

Other interactions of KCNE3

• The results suggest that KCNQ1, probably with KCNE2 or KCNE3 as its accessory unit, provides a significant fraction of IKvol in rat hepatocytes [12].
• Namely I(ks), the slowly activating delayed rectifier current, is produced by KvLQT1/KCNE1, whereas KvLQT1/KCNE3 yields a more rapidly activating current with a distinct constitutively active component [18].
• FHypoKPP is caused by mutations in ionic channel genes calcium (CACN1AS), sodium (SCN4A) and potassium (KCNE3) [3].

References