Orchestrating aquaporin-4 and connexin-43 expression in brain: Differential roles of α1- and β1-syntrophin

Rao, Shreyas Balachandra; Skauli, Nadia; Jovanović, Nenad; Katoozi, Shirin; Frigeri, Antonio; Froehner, Stanley C.; Adams, Marvin E.; Ottersen, Ole Petter; Amiry-Moghaddam, Mahmood

doi:10.1016/j.bbamem.2021.183616

Cited by 16 publications

(10 citation statements)

References 47 publications

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“…The polarized distribution has been attributed to the presence of scaffolding molecules to which AQP4 binds with high affinity, primarily dystrophin/syntrophin (see 40 ), and one role of the readthrough extension of AQP4ex may be to anchor this isoform in the endfoot through interactions with syntrophin and other scaffolds 17 . Recent studies using mice in which AQP4ex or syntrophin isoforms were deleted have revealed that AQPex expression appears to reciprocally localize α-syntophin at the endfoot and that deletion of both syntrophin isoforms leads to loss of AQP4 at the endfoot 17 , 41 . An additional finding from the study on syntrophin deletion was that endfoot AQP4 OAPs were smaller, while Cx43 plaques increased in size 41 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies using mice in which AQP4ex or syntrophin isoforms were deleted have revealed that AQPex expression appears to reciprocally localize α-syntophin at the endfoot and that deletion of both syntrophin isoforms leads to loss of AQP4 at the endfoot 17 , 41 . An additional finding from the study on syntrophin deletion was that endfoot AQP4 OAPs were smaller, while Cx43 plaques increased in size 41 . In addition to preferential adhesion to scaffolding proteins as a mechanism that enhances endfoot expression of AQP4 and especially the AQP4ext isoform, it has recently been reported that local translation of certain astrocyte proteins occurs in endfeet 42 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability

Cibelli

Stout

Timmermann

et al. 2021

Sci Rep

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The neurovascular unit (NVU) consists of cells intrinsic to the vessel wall, the endothelial cells and pericytes, and astrocyte endfeet that surround the vessel but are separated from it by basement membrane. Endothelial cells are primarily responsible for creating and maintaining blood–brain-barrier (BBB) tightness, but astrocytes contribute to the barrier through paracrine signaling to the endothelial cells and by forming the glia limitans. Gap junctions (GJs) between astrocyte endfeet are composed of connexin 43 (Cx43) and Cx30, which form plaques between cells. GJ plaques formed of Cx43 do not diffuse laterally in the plasma membrane and thus potentially provide stable organizational features to the endfoot domain, whereas GJ plaques formed of other connexins and of Cx43 lacking a large portion of its cytoplasmic carboxyl terminus are quite mobile. In order to examine the organizational features that immobile GJs impose on the endfoot, we have used super-resolution confocal microscopy to map number and sizes of GJ plaques and aquaporin (AQP)-4 channel clusters in the perivascular endfeet of mice in which astrocyte GJs (Cx30, Cx43) were deleted or the carboxyl terminus of Cx43 was truncated. To determine if BBB integrity was compromised in these transgenic mice, we conducted perfusion studies under elevated hydrostatic pressure using horseradish peroxide as a molecular probe enabling detection of micro-hemorrhages in brain sections. These studies revealed that microhemorrhages were more numerous in mice lacking Cx43 or its carboxyl terminus. In perivascular domains of cerebral vessels, we found that density of Cx43 GJs was higher in the truncation mutant, while GJ size was smaller. Density of perivascular particles formed by AQP4 and its extended isoform AQP4ex was inversely related to the presence of full length Cx43, whereas the ratio of sizes of the particles of the AQP4ex isoform to total AQP4 was directly related to the presence of full length Cx43. Confocal analysis showed that Cx43 and Cx30 were substantially colocalized in astrocyte domains near vasculature of truncation mutant mice. These results showing altered distribution of some astrocyte nexus components (AQP4 and Cx30) in Cx43 null mice and in a truncation mutant, together with leakier cerebral vasculature, support the hypothesis that localization and mobility of gap junction proteins and their binding partners influences organization of astrocyte endfeet which in turn impacts BBB integrity of the NVU.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability

Cibelli

Stout

Timmermann

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Together, AQP4 and GJ channels connect astrocytes into a water-equilibrating network, where the GJconnected glia extends from arteriolar astrocyte endfeet that take up water, glucose and other solutes, across brain parenchyma, where water balance is maintained and energy substrates are delivered, to venous perivascular astrocyte endfeet where efflux of excess water and metabolites occurs into the circulation. Location, expression and function of AQP4 and GJs are interdependent, as indicated by our initial studies of AQP4 siRNA effects on Cx43 in astrocytes 51 and confirmed by more recent examination of transgenic mice in which either AQP4 4,45,52 or Cx43 53 is manipulated. Such interdependence likely provides a major mechanism by which water and solute homeostasis is achieved, and disruption of normal distribution of these two proteins impacts brain edema and BBB permeability 54 .…”

Section: Discussionmentioning

confidence: 57%

“…An additional finding from the study on syntrophin deletion was that endfoot AQP4 OAPs were smaller, while Cx43 plaques increased in size 45 . In addition to preferential adhesion to scaffolding proteins as a mechanism that enhances endfoot expression of AQP4 and especially the AQP4 isoform, it has recently been reported that local translation of certain astrocyte proteins occurs in endfeet 46 .…”

Section: Discussionmentioning

confidence: 96%

“…The polarized distribution has been attributed to the presence of scaffolding molecules to which AQP4 binds with high affinity, primarily dystrophin/syntrophin (see 44 ), and one role of the readthrough extension of AQP4ex may be to anchor this isoform in the endfoot through interactions with syntrophin and other scaffolds 21 . Recent studies using mice in which AQP4ex or syntrophin isoforms were deleted have revealed that AQPex expression appears to reciprocally localize αsyntophin at the endfoot and that deletion of both syntrophin isoforms leads to loss of AQP4 at the endfoot 21,45 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability

Cibelli

Stout

Timmermann

et al. 2021

Preprint

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The neurovascular unit (NVU) consists of cells intrinsic to the vessel wall, the endothelial cells and pericytes, and astrocyte endfeet that surround the vessel but are separated from it by basement membrane. Endothelial cells are primarily responsible for creating and maintaining blood-brain-barrier (BBB) tightness, but astrocytes contribute to the barrier through paracrine signaling to the endothelial cells and by forming the glia limitans. Gap junctions (GJs) between astrocyte endfeet are composed of connexin 43 (Cx43) and Cx30, which form plaques between cells. GJ plaques formed of Cx43 do not diffuse laterally in the plasma membrane and thus potentially provide stable organizational features to the endfoot domain, whereas GJ plaques formed of other connexins and of Cx43 lacking a large portion of its cytoplasmic carboxyl terminus are quite mobile. In order to examine the organizational features that immobile GJs impose on the endfoot, we have used super-resolution confocal microscopy to map number and sizes of GJ plaques and aquaporin (AQP)-4 channel clusters in the perivascular endfeet of mice in which astrocyte GJs (Cx30, Cx43) were deleted or the carboxyl terminus of Cx43 was truncated. To determine if blood-brain-barrier integrity was compromised in these transgenic mice, we conducted perfusion studies under elevated hydrostatic pressure using horseradish peroxide as a molecular probe enabling detection of micro-hemorrhages in brain sections. These studies revealed that microhemorrhages were more numerous in mice lacking Cx43 or its carboxyl terminus. In perivascular domains of cerebral vessels, we found that density of Cx43 GJs was higher in the truncation mutant, while GJ size was smaller. Density of perivascular particles formed by AQP4 and its extended isoform AQP4ex was inversely related to the presence of full length Cx43, whereas the ratio of sizes of the particles of the AQP4ex isoform to total AQP4 was directly related to the presence of full length Cx43. Confocal analysis showed that Cx43 and Cx30 were substantially colocalized in astrocyte domains near vasculature of truncation mutant mice. These results showing altered distribution of some astrocyte nexus components (AQP4 and Cx30) in Cx43 null mice and in a truncation mutant, together with leakier cerebral vasculature, support the hypothesis that localization and mobility of gap junction proteins and their binding partners influences organization of astrocyte endfeet which in turn impacts BBB integrity of the NVU.

show abstract

Aquaporins in Cardiovascular System

Fan

et al. 2023

Advances in Experimental Medicine and Biology

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Orchestrating aquaporin-4 and connexin-43 expression in brain: Differential roles of α1- and β1-syntrophin

Cited by 16 publications

References 47 publications

Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability

Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability

Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability

Aquaporins in Cardiovascular System

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