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The central role of aquaporins in the pathophysiology of ischemic stroke.

Vella J, Zammit C, Di Giovanni G, Muscat R, Valentino M - Front Cell Neurosci (2015)

Bottom Line: AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome.AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction.AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biochemistry, University of Malta Msida, Malta.

ABSTRACT
Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4- mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.

No MeSH data available.


Related in: MedlinePlus

Aquaporin structure. (A) Generalized schematic of AQP family proteins expanded to show connectivity. (B) Generalized schematic of AQP family protein structure collapsed to show protein folding, wide arrow indicates the approximate substrate path. (C) Generalized schematic of AQP biological unit, wide arrows indicate substrate path; the narrow arrow indicates the proposed path of dissolved gasses through the central pore. Reproduced with permission from Huber et al. (2012).
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Figure 3: Aquaporin structure. (A) Generalized schematic of AQP family proteins expanded to show connectivity. (B) Generalized schematic of AQP family protein structure collapsed to show protein folding, wide arrow indicates the approximate substrate path. (C) Generalized schematic of AQP biological unit, wide arrows indicate substrate path; the narrow arrow indicates the proposed path of dissolved gasses through the central pore. Reproduced with permission from Huber et al. (2012).

Mentions: The members of the AQP water channels consist of small (~30 kDa/monomer) hydrophobic, integral membrane proteins. These are expressed widely in the animal and plant kingdoms with 13 subtypes having been identified so far in mammals. The existence of a channel pore for water was hypothesized before the identification of the protein and was based on observations that red blood cells have higher water permeability than expected for an equivalent surface area of a lipid bilayer membrane. This hypothesis was confirmed in 1992 by Peter Agre and colleagues with the identification of AQP0, the first member of the AQP family of water channels (Preston et al., 1992). Besides functioning as a water channel, APQ0 also has a structural role, being required to maintain the transparency and optical accommodation of the ocular lens. The monomeric units of AQPs consist of six transmembrane α-helices (M1, M2, M4–M7, and M8), two half helices (M3 and M7) and five connecting loops around a water pore (Figure 3). Their specificity for water may depend on two conserved Asn-Pro-Ala (NPA) motifs in the half helices M3 and M7, which contain inward-facing asparagine polar side chains that prevent proton conduction (Murata et al., 2000). Together with the α-carbonyl groups, the NPA motifs act as hydrogen-bond donors and acceptors that allow the transport of water or glycerol through the pore (Fu et al., 2000; Sui et al., 2001). Molecular simulations based on the AQP1 crystal structure suggest single-file passage of water through the narrow <0.3 nm pore, in which steric and electrostatic factors prevent transport of protons and other small molecules (Sui et al., 2001). AQPs have no gating system for water permeability through their channel pore and therefore functions of APQs depend on their level of expression in the plasma membrane. The transport function of many AQPs can be inhibited by non-specific, mercurial sulfhydryl-reactive compounds, such as mercury chloride and there is growing interest in the design of non-toxic, AQP-selective inhibitors (Verkman, 2001; Castle, 2005).


The central role of aquaporins in the pathophysiology of ischemic stroke.

Vella J, Zammit C, Di Giovanni G, Muscat R, Valentino M - Front Cell Neurosci (2015)

Aquaporin structure. (A) Generalized schematic of AQP family proteins expanded to show connectivity. (B) Generalized schematic of AQP family protein structure collapsed to show protein folding, wide arrow indicates the approximate substrate path. (C) Generalized schematic of AQP biological unit, wide arrows indicate substrate path; the narrow arrow indicates the proposed path of dissolved gasses through the central pore. Reproduced with permission from Huber et al. (2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389728&req=5

Figure 3: Aquaporin structure. (A) Generalized schematic of AQP family proteins expanded to show connectivity. (B) Generalized schematic of AQP family protein structure collapsed to show protein folding, wide arrow indicates the approximate substrate path. (C) Generalized schematic of AQP biological unit, wide arrows indicate substrate path; the narrow arrow indicates the proposed path of dissolved gasses through the central pore. Reproduced with permission from Huber et al. (2012).
Mentions: The members of the AQP water channels consist of small (~30 kDa/monomer) hydrophobic, integral membrane proteins. These are expressed widely in the animal and plant kingdoms with 13 subtypes having been identified so far in mammals. The existence of a channel pore for water was hypothesized before the identification of the protein and was based on observations that red blood cells have higher water permeability than expected for an equivalent surface area of a lipid bilayer membrane. This hypothesis was confirmed in 1992 by Peter Agre and colleagues with the identification of AQP0, the first member of the AQP family of water channels (Preston et al., 1992). Besides functioning as a water channel, APQ0 also has a structural role, being required to maintain the transparency and optical accommodation of the ocular lens. The monomeric units of AQPs consist of six transmembrane α-helices (M1, M2, M4–M7, and M8), two half helices (M3 and M7) and five connecting loops around a water pore (Figure 3). Their specificity for water may depend on two conserved Asn-Pro-Ala (NPA) motifs in the half helices M3 and M7, which contain inward-facing asparagine polar side chains that prevent proton conduction (Murata et al., 2000). Together with the α-carbonyl groups, the NPA motifs act as hydrogen-bond donors and acceptors that allow the transport of water or glycerol through the pore (Fu et al., 2000; Sui et al., 2001). Molecular simulations based on the AQP1 crystal structure suggest single-file passage of water through the narrow <0.3 nm pore, in which steric and electrostatic factors prevent transport of protons and other small molecules (Sui et al., 2001). AQPs have no gating system for water permeability through their channel pore and therefore functions of APQs depend on their level of expression in the plasma membrane. The transport function of many AQPs can be inhibited by non-specific, mercurial sulfhydryl-reactive compounds, such as mercury chloride and there is growing interest in the design of non-toxic, AQP-selective inhibitors (Verkman, 2001; Castle, 2005).

Bottom Line: AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome.AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction.AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biochemistry, University of Malta Msida, Malta.

ABSTRACT
Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4- mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.

No MeSH data available.


Related in: MedlinePlus