H95 Is a pH-Dependent Gate in Aquaporin 4

Abstract

Aquaporin 4 (AQP4) is a transmembrane protein from the aquaporin family and is the predominant water channel in the mammalian brain. The regulation of permeability of this protein could be of potential therapeutic use to treat various forms of damage to the nervous tissue. In this work, based on data obtained from in silico and in vitro studies, a pH sensitivity that regulates the osmotic water permeability of AQP4 is demonstrated. The results indicate that AQP4 has increased water permeability at conditions of low pH in atomistic computer simulations and experiments carried out on Xenopus oocytes expressing AQP4. With molecular dynamics simulations, this effect was traced to a histidine residue (H95) located in the cytoplasmic lumen of AQP4. A mutant form of AQP4, in which H95 was replaced with an alanine (H95A), loses sensitivity to cytoplasmic pH changes in in vitro osmotic water permeability, thereby substantiating the in silico work.

Gating in plant plasma membrane aquaporins: the involvement of leucine in the formation of a pore constriction in the closed state

“…3, in BvPIP2;2 the pore radius at the Ar/R region is of approximately 0. 72 A, a similar value was previously reported for SoPIP2;1 [10] and other aquaporins [6,23,36] (Fig. 3A).…”

“…The triggering events that promote the open-closed transition in PIP channels can be a drop in cytoplasmic pH, an increase in Ca 2+ concentrations or the dephosphorylation of specific serine residues [17][18][19][20][21][22]. Permeability regulation by pH has been reported for different aquaporins such as mammalian AQP3, AQP4, AQP5, AQP7 and plant AtTIP2;1, VvTIP2;1 among others [23][24][25][26][27][28]. But in particular, cytosolic acidification is a well-studied trigger for PIP channels gating as pH regulation of water transport has been described in red beet, Arabidopsis thaliana, strawberry, grape, and tobacco PIP aquaporins [17,20,[29][30][31][32][33].…”

Temperature dependence of protein-water interactions in a gated yeast aquaporin

“…An even more rapid change in water transport activity can be achieved by gating 7,8 whereby the water conducting pore of a gated aquaporin can be opened or closed through mechanical means, analogous to the opening and closing of a bottle with a hinged cap 9 . Aquaporin gating may be triggered by diverse types of external stimuli, including phosphorylation 10,11 and pH 10,12,13 . Voltage 14 and membrane-mediated mechanical stress 11 have also been suggested as external factors inducing aquaporin gating.…”

Rat Aquaporin-5 Is pH-Gated Induced by Phosphorylation and Is Implicated in Oxidative Stress

“…The relative stability of the two resulting states, open and closed, may depend on small changes in the microenvironment, such as variations of pH. Indeed, a pH-dependent gating mechanism was recently obtained from in silico and in vitro studies [35], ascribing to His95 located in AQP4 cytoplasmic end the role of regulating channel permeability. Phosphorylation of AQP4 has also been demonstrated with opposed effects depending on the residue that is phosphorylated.…”