Aquaporin-4 in the central nervous system: Cellular and subcellular distribution and coexpression with KIR4.1

doi:10.1016/j.neuroscience.2004.08.053

Neuroscience

Volume 129, Issue 4, 2004, Pages 905-913

https://doi.org/10.1016/j.neuroscience.2004.08.053 Get rights and content

Abstract

Aquaporin-4 (AQP4) is the predominant water channel in the neuropil of the central nervous system. It is expressed primarily in astrocytes, but also occurs in ependymocytes and endothelial cells. A striking feature of AQP4 expression is its polarized distribution in brain astrocytes and retinal Müller cells. Thus, immunogold analyses have revealed an enrichment of AQP4 in endfeet membranes in contact with brain microvessels or subarachnoidal space and a low but significant concentration in non-endfeet membranes, including those astrocyte membranes that ensheath glutamate synapses. The subcellular compartmentation of AQP4 mimics that of the potassium channel Kir4.1, which is implicated in spatial buffering of K⁺. We propose that AQP4 works in concert with Kir4.1 and the electrogenic bicarbonate transporter NBC and that water flux through AQP4 contributes to the activity dependent volume changes of the extracellular space. Such volume changes are important as they affect the extracellular solute concentrations and electrical fields, and hence neuronal excitability. We conclude that AQP4-mediated water flux represents an integral element of brain volume and ion homeostasis.

Section snippets

Distribution of AQP4 in the central nervous system

Immunocytochemical analyses have shown that AQP4 occurs primarily in astrocytes (Fig. 1, Fig. 2) and that neurons do not contain detectable levels of this protein (Nielsen et al., 1997; Nagelhus et al., 1998). This has been confirmed by in situ hybridization analyses with probes specific for AQP4 mRNA (Nagelhus et al., 1998).

AQP4 is also expressed (at lower levels than in astrocytes) in endothelial cells (Nagelhus et al., 1998; Kobayashi et al., 2001; Amiry-Moghaddam et al., 2004) and

Physiological data support the idea that astrocytes mediate a redistribution of water

It is well known that neuronal activity is associated with a shrinkage of the extracellular space around the active synapses (Dietzel et al., 1980; Sykova and Chvatal, 2000). This must imply a cellular uptake of water. In a series of studies in acute cortical slices, Holthoff and Witte (1996, 2000) demonstrated that the shrinkage at the site of neuronal activation was accompanied by an enhancement of the extracellular space volume at more distant sites. Specifically, high frequency stimulation

AQP4 plays a physiological role in spatial K⁺ buffering

It follows from the above that the astrocyte can be viewed as a cell that is equipped with two serially coupled membrane domains in regard to water transport. In other words, the polarized expression of AQP4, which allows bidirectional transport of water (Agre et al., 2002), reflects a polarization of function with respect to the direction of water flux (influx in one domain is associated with efflux in the other). This arrangement is highly reminiscent of the polarized expression of K⁺

A novel hypothesis: AQP4 mediates activity dependent volume changes that are driven by bicarbonate transport

As discussed above, three lines of evidence point to a coupling between AQP4 and K⁺ spatial buffering. These are:

• AQP4 shows a precise colocalization with Kir4.1

• K⁺ spatial buffering is accompanied by changes in extracellular space volume, indicative of rapid transmembrane water transport through the plasma membranes of AQP4-expressing astrocytes

• K⁺ clearance is delayed in animals that lack perivascular AQP4

How can the coupling between K⁺ buffering and water transport be explained in

Possible effects of an AQP4 mediated shrinkage of the extracellular space

The physiological effects of activity dependent volume changes have been discussed by several authors (Jefferys, 1995; Payne et al., 2003). One obvious effect is that the local shrinkage of extracellular space will temporarily restrict the diffusion of signal substances and other solutes in the area of neuronal activity. One would expect that these changes would reduce the extent of transmitter spillover in synapses. Perhaps more importantly, removal of water from the extracellular space will

Perspectives

An interesting implication of the above scenario is that AQP4, through regulation of extracellular space volume, will modulate neuronal transmission and excitability. Evidence for this has been obtained in AQP4^−/− animals, which show an increased seizure threshold (Binder et al., 2004). Based on our studies of α-syn^−/− animals discussed above (Amiry-Moghaddam et al., 2003, 2004; Amiry-Moghaddam and Ottersen, 2003) we postulate that the increased threshold reflects a blunting of the activity

Acknowledgments

We thank Kai Kaila and Juha Voipio for valuable comments on the manuscript and Gunnar Lothe and Carina Knudsen for excellent technical assistance.

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Aquaporin-4 in the central nervous system: Cellular and subcellular distribution and coexpression with KIR4.1

Abstract

Section snippets

Distribution of AQP4 in the central nervous system

Physiological data support the idea that astrocytes mediate a redistribution of water

AQP4 plays a physiological role in spatial K+ buffering

A novel hypothesis: AQP4 mediates activity dependent volume changes that are driven by bicarbonate transport

Possible effects of an AQP4 mediated shrinkage of the extracellular space

Perspectives

Acknowledgments

J Biol Chem

Neurosci Lett

Trends Neurosci

Neurochem Int

Aquaporin water channels-from atomic structure to clinical medicine

J Physiol

The molecular basis of water transport in the brain

Nat Rev Neurosci

Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice

Proc Natl Acad Sci USA

Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood-brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia

FASEB J

Increased seizure threshold in mice lacking aquaporin-4 water channels

Neuroreport

Regulation and modulation of pH in the brain

Physiol Rev

Transient changes in the size of the extracellular space in the sensorimotor cortex of cats in relation to stimulus-induced changes in potassium concentration

Exp Brain Res

Localization of MIWC and GLIP water channel homologs in neuromuscular, epithelial and glandular tissues

J Cell Sci

Intrinsic optical signals in rat neocortical slices measured with near-infrared dark-field microscopy reveal changes in extracellular space

J Neurosci

Directed spatial potassium redistribution in rat neocortex

Glia

Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions

Physiol Rev

Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance

Proc Natl Acad Sci USA

AQP4 plays a physiological role in spatial K⁺ buffering

Delayed K⁺ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice