High impact information on Kcnk18

• Mutations of the PQIVID sequence of TRESK to PQIVIA, PQIVAD, or PQAVAD increasingly deteriorated the calcium-dependent activation in the listed order and correspondingly reduced the benzocaine sensitivity (a property discriminating activated channels from resting ones), when it was measured after the calcium signal in Xenopus oocytes [1].
• In its intracellular loop, mouse TRESK possesses the amino acid sequence, PQIVID, which is similar to the calcineurin binding consensus motif, PXIXIT (where X denotes any amino acids), necessary for NFAT (nuclear factor of activated T cells) activation and nuclear translocation [1].
• The two-pore domain K(+) channel, TRESK (TWIK-related spinal cord K(+) channel) is activated in response to the calcium signal by the calcium/calmodulin-dependent protein phosphatase, calcineurin [1].
• Wild type calcineurin was recruited to GST-TRESK-loop in the presence of calcium and calmodulin [1].
• Immunosuppressive compounds, developed to target the NFAT binding site of calcineurin, are also expected to interfere with TRESK regulation, in addition to their desired effect on NFAT [1].

Biological context of Kcnk18

• The new K(2P) channel was named TRESK-2, as its amino acid sequence shares 65% identity with that of TRESK-1 [2].
• Serine 276 was identified as the major functional target of calcineurin in TRESK by alanine-scanning mutagenesis [3].
• Mibefradil, zinc, and mercuric ions inhibited TRESK expressed in Xenopus laevis oocytes with IC50 values lower than 10 microM [4].

Anatomical context of Kcnk18

• TRESK, a recently described member of the two-pore domain potassium (2PK(+)) channel family, was activated 5-15-fold after stimulation of various Ca(2+)-mobilizing receptors in Xenopus oocytes [3].
• In COS-7 cells transfected with TRESK-2 DNA, a time-independent and noninactivating K+-selective current was recorded [2].
• In the rat, TRESK-2 mRNA transcripts were expressed abundantly in the thymus and spleen and at low levels in many other tissues, including heart, small intestine, skeletal muscle, uterus, testis, and placenta, as judged by Northern blot analysis [2].

Associations of Kcnk18 with chemical compounds

• However, application of Ca(2+) to inside-out membrane patches failed to influence TRESK single channel activity, suggesting that cytoplasmic factors are also required for the regulation [3].
• In inside-out patches, TRESK-2 was unaffected by the intracellular application of 10 microm guanosine 5'-O-(thiotriphosphate) [2].
• TRESK-2 was insensitive to 1 mm tetraethylammonium, 100 nm apamin, 1 mm 4-aminopyridine, and 10 microm glybenclamide [2].
• Extracellular application of ionomycin, as well as the microinjection of inositol 1,4,5-trisphosphate or calcium, also evoked TRESK activation, whereas microinjection of EGTA or pretreatment of the oocytes with thapsigargin prevented the receptor-mediated effect [3].
• Cyclosporin A and FK506, specific inhibitors of the calcium/calmodulin-dependent protein phosphatase (calcineurin), completely eliminated TRESK activation [3].

Analytical, diagnostic and therapeutic context of Kcnk18

• Reverse transcriptase PCR showed that, among nine K2P channels tested, TASK-1, TASK-2, TASK-3, TREK-2, and TRESK-2 were expressed in MIN6 cells [5].

References