Twins Don’t Always Act Alike

Science Signaling  01 Sep 2009:
Vol. 2, Issue 86, pp. ec292
DOI: 10.1126/scisignal.286ec292

As the names imply, the TREK1 and TREK2 two pore-domain potassium channels are closely related: They have similar sequences, and both are activated by stretch, polyunsaturated fatty acids, and intracellular acidification and inhibited by phosphorylation of conserved intracellular residues. Sandoz et al. investigated the sensitivity of these two TREK channels to extracellular pH and found that, as had previously been reported, current through TREK1 channels was inhibited by external acidification. At an extracellular pH of 6.9, current through mouse TREK1 channels heterologously expressed in Xenopus oocytes was reduced compared with that at pH 7.4; at pH 8, current was enhanced. Current sensitivity to external pH was independent of voltage and was apparent in channels constitutively activated through mutation of an internal residue or when channels were coexpressed with A kinase anchoring protein (AKAP) 150, which activates TREK1 channels by binding to them internally. Exposure to diethyl pyrocarbonate (DEPC) inhibited the effects of external pH on TREK1 current, suggesting that one or more extracellular histidine residues were likely involved in the response, and mutational analysis specifically implicated histidine 126. Although current through TREK2 was also sensitive to pH changes in the same range, intriguingly, current through TREK2 was activated by acidification. Histidine 126 in TREK1 is conserved as histidine 151 in TREK2, and mutational analysis indicated that TREK2 activation by external acidification depended on this conserved residue. Analyses of chimeric channels containing various regions of TREK1 and TREK2 indicated that their differential response to acidification depended on residues in an extracellular region after the second pore domain and before the fourth membrane-spanning domain. A combination of structural modeling and mutational analysis suggested that electrostatic interactions with charged residues determined the response to protonation of the conserved histidine. Thus, these two very similar channels show opposite responses to changes in external pH.

G. Sandoz, D. Douguet, F. Chatelain, M. Lazdunski, F. Lesage, Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue. Proc. Natl. Acad. Sci. USA 106, 14628–14633 (2009). [Abstract] [Full Text]