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Water permeability of aquaporin-4 channel depends on bilayer composition, thickness, and elasticity.

ABSTRACT: Aquaporin-4 (AQP4) is the primary water channel in the mammalian brain, particularly abundant in astrocytes, whose plasma membranes normally contain high concentrations of cholesterol. Here we test the hypothesis that the water permeabilities of two naturally occurring isoforms (AQP4-M1 and AQP4-M23) depend on bilayer mechanical/structural properties modulated by cholesterol and phospholipid composition. Osmotic stress measurements were performed with proteoliposomes containing AQP4 and three different lipid mixtures: 1), phosphatidylcholine (PC) and phosphatidylglycerol (PG); 2), PC, PG, with 40 mol % cholesterol; and 3), sphingomyelin (SM), PG, with 40 mol % cholesterol. The unit permeabilities of AQP4-M1 were 3.3 ± 0.4 × 10(-13) cm(3)/s (mean ± SE), 1.2 ± 0.1 × 10(-13) cm(3)/s, and 0.4 ± 0.1 × 10(-13) cm(3)/s in PC:PG, PC:PG:cholesterol, and SM:PG:cholesterol, respectively. The unit permeabilities of AQP4-M23 were 2.1 ± 0.2 × 10(-13) cm(3)/s, 0.8 ± 0.1 × 10(-13) cm(3)/s, and 0.3 ± 0.1 × 10(-13) cm(3)/s in PC:PG, PC:PG:cholesterol, and SM:PG:cholesterol, respectively. Thus, for each isoform the unit permeabilities strongly depended on bilayer composition and systematically decreased with increasing bilayer compressibility modulus and bilayer thickness. These observations suggest that altering lipid environment provides a means of regulating water channel permeability. Such permeability changes could have physiological consequences, because AQP4 water permeability would be reduced by its sequestration into SM:cholesterol-enriched raft microdomains. Conversely, under ischemic conditions astrocyte membrane cholesterol content decreases, which could increase AQP4 permeability.

SUBMITTER: Tong J

PROVIDER: S-EPMC3491688 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Water permeability of aquaporin-4 channel depends on bilayer composition, thickness, and elasticity.

Tong Jihong J Briggs Margaret M MM McIntosh Thomas J TJ

Biophysical journal 20121101 9

Aquaporin-4 (AQP4) is the primary water channel in the mammalian brain, particularly abundant in astrocytes, whose plasma membranes normally contain high concentrations of cholesterol. Here we test the hypothesis that the water permeabilities of two naturally occurring isoforms (AQP4-M1 and AQP4-M23) depend on bilayer mechanical/structural properties modulated by cholesterol and phospholipid composition. Osmotic stress measurements were performed with proteoliposomes containing AQP4 and three di ...[more]

PMID: 23199918

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Project description:Aquaporin-4 (AQP4), the primary water channel in glial cells of the mammalian brain, plays a critical role in water transport in the central nervous system. Previous experiments have shown that the water permeability of AQP4 depends on the cholesterol content in the lipid bilayer, but it was not clear whether changes in permeability were due to direct cholesterol-AQP4 interactions or to indirect effects caused by cholesterol-induced changes in bilayer elasticity or bilayer thickness. To determine the effects resulting only from bilayer thickness, here we use a combination of experiments and simulations to analyze AQP4 in cholesterol-free phospholipid bilayers with similar elastic properties but different hydrocarbon core thicknesses previously determined by x-ray diffraction. The channel (unit) water permeabilities of AQP4 measured by osmotic-gradient experiments were 3.5 ± 0.2 × 10(-13) cm(3)/s (mean ± SE), 3.0 ± 0.3 × 10(-13) cm(3)/s, 2.5 ± 0.2 × 10(-13) cm(3)/s, and 0.9 ± 0.1 × 10(-13) cm(3)/s in bilayers containing (C22:1)(C22:1)PC, (C20:1)(C20:1)PC, (C16:0)(C18:1)PC, and (C13:0)(C13:0)PC, respectively. Channel permeabilities obtained by molecular dynamics (MD) simulations were 3.3 ± 0.1 × 10(-13) cm(3)/s and 2.5 ± 0.1 × 10(-13) cm(3)/s in (C22:1)(C22:1)PC and (C14:0)(C14:0)PC bilayers, respectively. Both the osmotic-gradient and MD-simulation results indicated that AQP4 channel permeability decreased with decreasing bilayer hydrocarbon thickness. The MD simulations also suggested structural modifications in AQP4 in response to changes in bilayer thickness. Although the simulations showed no appreciable changes to the radius of the pore located in the hydrocarbon region of the bilayers, the simulations indicated that there were changes in both pore length and ?-helix organization near the cytoplasmic vestibule of the channel. These structural changes, caused by mismatch between the hydrophobic length of AQP4 and the bilayer hydrocarbon thickness, could explain the observed differences in water permeability with changes in bilayer thickness.

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Water permeability of aquaporin-4 channel depends on bilayer composition, thickness, and elasticity.

Publications

Water permeability of aquaporin-4 channel depends on bilayer composition, thickness, and elasticity.

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