Identification and Molecular Mechanisms of the Rapid Tonicity-induced Relocalization of the Aquaporin 4 Channel

Kitchen, Philip; Day, Rebecca E.; Taylor, Luke H. J.; Salman, Mootaz M.; Bill, Roslyn M.; Conner, Matthew T.; Conner, Alex C.

doi:10.1074/jbc.m115.646034

Cited by 93 publications

(123 citation statements)

References 35 publications

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“…Cell surface AQP4 expression after 4 h mild hypothermia (32 °C) was compared to cells at 37 °C using an AQP4 biotinylation assay [as described in our previous study (Kitchen et al ., )]. The results show that despite there being no change in total AQP4 protein levels (Fig.…”

Section: Resultsmentioning

confidence: 78%

Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium/transient receptor potential vanilloid 4 (TRPV4)‐ and calmodulin‐mediated mechanism

Salman

Kitchen

Woodroofe

et al. 2017

Eur J of Neuroscience

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Human aquaporin 4 (AQP4) is the primary water channel protein in brain astrocytes. Hypothermia is known to cause astrocyte swelling in culture, but the precise role of AQP4 in this process is unknown. Primary human cortical astrocytes were cultured under hypothermic (32°C) or normothermic (37°C) conditions. AQP4 transcript, total protein and surface-localized protein were quantified using RT-qPCR, sandwich ELISA with whole cell lysates or cell surface biotinylation, followed by ELISA analysis of the surface-localized protein, respectively. Four-hour mild hypothermic treatment increased the surface localization of AQP4 in human astrocytes to 155 AE 4% of normothermic controls, despite no change in total protein expression levels. The hypothermiamediated increase in AQP4 surface abundance on human astrocytes was blocked using either calmodulin antagonist (trifluoperazine, TFP); TRPV4 antagonist, HC-067047 or calcium chelation using EGTA-AM. The TRPV4 agonist (GSK1016790A) mimicked the effect of hypothermia compared with untreated normothermic astrocytes. Hypothermia led to an increase in surface localization of AQP4 in human astrocytes through a mechanism likely dependent on the TRPV4 calcium channel and calmodulin activation. Understanding the effects of hypothermia on astrocytic AQP4 cell surface expression may help develop new treatments for brain swelling based on an in-depth mechanistic understanding of AQP4 translocation.

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Section: Resultsmentioning

confidence: 78%

Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium/transient receptor potential vanilloid 4 (TRPV4)‐ and calmodulin‐mediated mechanism

Salman

Kitchen

Woodroofe

et al. 2017

Eur J of Neuroscience

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“…In addition to measuring astrocyte Ca 2+ dynamics, we investigated the potential of sex differences in the location of astrocyte AQP4 and S100β, proteins suspected to play a role in brain injury after ischemic stroke (Benfenati et al, 2011; Donato et al, 2009; Kitchen et al, 2015; Vella et al, 2015). Under physiological conditions, AQP4 is highly polarized to astrocyte endfeet rather than non-endfeet processes and/or soma (Potokar et al, 2013).…”

Section: 3 Discussionmentioning

confidence: 99%

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

Morrison

Filosa

2016

Neuroscience

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Epidemiological studies report that infarct size is decreased and stroke outcomes are improved in young females when compared to males. However, mechanistic insight is lacking. We posit that sex-specific differences in glial cell functions occurring immediately after ischemic stroke are a source of dichotomous outcomes. In this study we assessed astrocyte Ca2+ dynamics, aquaporin 4 (AQP4) polarity, S100β expression pattern, as well as, microglia morphology and phagocytic marker CD11b in male and female mice following 60 minutes of middle cerebral artery (MCA) occlusion. We reveal sex differences in the frequency of intracellular astrocyte Ca2+ elevations (F(1,86)=8.19, P=0.005) and microglia volume (F(1,40)=12.47, P=0.009) immediately following MCA occlusion in acute brain slices. Measured in fixed tissue, AQP4 polarity was disrupted (F(5,86)=3.30, P=0.009) and the area of non-S100β immunoreactivity increased in ipsilateral brain regions after 60 min of MCA occlusion (F(5,86)=4.72, P=0.007). However, astrocyte changes were robust in male mice when compared to females. Additional sex differences were discovered regarding microglia phagocytic receptor CD11b. In sham mice, constitutively high CD11b immunofluorescence was observed in females when compared to males (P=0.03). When compared to sham, only male mice exhibited an increase in CD11b immunoreactivity after MCA occlusion (P=0.006). We posit that a sex difference in the presence of constitutive CD11b has a role in determining male and female microglia phagocytic responses to ischemia. Taken together, these findings are critical to understanding potential sex differences in glial physiology as well as stroke pathobiology which are foundational for the development of future sex-specific stroke therapies.

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“…Currently, multiple investigations have revealed the multi-faceted role of astrocytes in cerebral parenchymal homeostasis, which depends on intercellular communication (Dallérac et al, 2013). It has been widely reported that astrocytic cells play protective roles in the nervous system, characterized by the ion buffering (Walz, 2000; D’Ambrosio et al, 2002), the uptake and synthesis of neurotransmitters (Danbolt, 2001; Kaczor et al, 2015), controlling cerebral blood flow (Abbott et al, 2006; Newman, 2015), transport of water (Zeng et al, 2007; Kitchen et al, 2015), release of antioxidant substances (Pentreath and Slamon, 2000), and immunomodulation (Dong and Benveniste, 2001). Also, it has recently been described that astrocytes are involved in adult neurogenesis (Mori et al, 2005; Buffo et al, 2008; Duan et al, 2015; Nato et al, 2015), making the astrocyte a highly complex cell ( Figure 1A ).…”

Section: Introductionmentioning

confidence: 99%

The Role of Astrocytes in Neuroprotection after Brain Stroke: Potential in Cell Therapy

Becerra-Calixto

Cardona‐Gómez

2017

Front. Mol. Neurosci.

190

151

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Astrocytes are commonly involved in negative responses through their hyperreactivity and glial scar formation in excitotoxic and/or mechanical injuries. But, astrocytes are also specialized glial cells of the nervous system that perform multiple homeostatic functions for the survival and maintenance of the neurovascular unit. Astrocytes have neuroprotective, angiogenic, immunomodulatory, neurogenic, and antioxidant properties and modulate synaptic function. This makes them excellent candidates as a source of neuroprotection and neurorestoration in tissues affected by ischemia/reperfusion, when some of their deregulated genes can be controlled. Therefore, this review analyzes pro-survival responses of astrocytes that would allow their use in cell therapy strategies.

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Identification and Molecular Mechanisms of the Rapid Tonicity-induced Relocalization of the Aquaporin 4 Channel

Cited by 93 publications

References 35 publications

Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium/transient receptor potential vanilloid 4 (TRPV4)‐ and calmodulin‐mediated mechanism

Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium/transient receptor potential vanilloid 4 (TRPV4)‐ and calmodulin‐mediated mechanism

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

The Role of Astrocytes in Neuroprotection after Brain Stroke: Potential in Cell Therapy

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