Korean J Physiol Pharmacol.  2020 Nov;24(6):555-561. 10.4196/kjpp.2020.24.6.555.

Dual regulatory effects of PI(4,5)P2 on TREK-2 K+ channel through antagonizing interaction between the alkaline residues (K330. and R355-357 ) in the cytosolic C-terminal helix

Affiliations
  • 1Department of Physiology, Seoul National University College of Medicine, Seoul, Korea
  • 2Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Korea
  • 3Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, Korea
  • 4Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea

Abstract

TWIK-related two-pore domain K+ channel-2 (TREK-2) has voltageindependent activity and shows additional activation by acidic intracellular pH (pH i ) via neutralizing the E332 in the cytoplasmic C terminal (Ct). We reported opposite regulations of TREK-2 by phosphatidylinositol 4,5-bisphosphate (PIP2 ) via the alkaline K330 and triple Arg residues (R355-357) inhibition and activation, respectively. The G334 between them appeared critical because its mutation (G334A) endowed hTREK-2 with tonic activity, similar to the mutation of the inhibitory K330 (K330 A). To further elucidate the role of putative bent conformation at G334 ,we compared the dual mutation forms, K330 A/G334 A and G334 A/R 355-7 A, showing higher and lower basal activity, respectively. The results suggested that the tonic activity of G334 A owes to a dominant influence from R355-7. Since there are additional triple Arg residues (R 377-9 ) distal to R355-7 , we also examined the triple mutant (G334A/R355-7 A/R377-9 A) that showed tonic inhibition same with G334 A/R 355-7 A. Despite the state of tonic inhibition, the activation by acidic pH i was preserved in both G 334 A/R355-7 A and G334 A/R 355-7A/R377-9 A, similar to the R355-7 A. Also, the inhibitory effect of ATP could be commonly demonstrated under the activation by acidic pH i in R355-7A, G334 A/R355-7 A, and G334 A/R355-7 A/R377-9 A. These results suggest that the putative bent conformation at G334 is important to set the tug-of-war between K330 and R355-7 in the PIP2 -dependent regulation of TREK-2.

Keyword

Amino acids; basic; C-terminal; PIP2; Tandem pore domain potassium channels; TREK-2
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