Water movements in the brain:role of aquaporins
Matthew J. Tait, Samira Saadoun, B. Anthony Bell and Marios C. Papadopoulos
Academic Neurosurgery Unit, St. George’s University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK
About 80% of the brain is water. This review discussestheimportanceofthethreebrainwater-channelproteins(AQP1, AQP4, AQP9) in brain physiology. AQP1 isexpressedinthechoroidplexusandparticipatesinform-ing cerebrospinal ﬂuid. AQP4, found in astrocyte footprocesses, glia limitans and ependyma, facilitates watermovement into and out of the brain, accelerates astro-cyte migration and alters neuronal activity. Recently,AQP4 autoantibodies were discovered in patients withneuromyelitis optica, a demyelinating disease, and arenow being used to diagnose this condition. AQP9 ispresent in some glia and neurons, but its function isunclear. Finally, we discuss how the discovery of AQPactivators and inhibitors will be the next major step inthis ﬁeld.Water channels: general properties
80% of the brain is water, relatively littleis known about brain water physiology. We now knowabout a family of water-channel proteins, called aquapor-ins (AQPs), which increase plasma membrane osmoticpermeability. The existence of AQPs was suspected long before their identiﬁcation from experiments showing thatred blood cell membranes are more permeable to waterthan expected from water diffusion through a lipid bilayer. In 1988, Peter Agre discovered the ﬁrst water channel,termed AQP1, and was awarded the Nobel Prize inchemistry in 2003. He subsequently showed that frog oocytes expressing AQP1 in their plasma membrane werefar more susceptible to osmotic lysis than nonexpressing oocytes, thus proving that AQP1 transports water. Todate, at least 13 AQPs have been found in mammals andmore than 300 in lower organisms.TheAQPsareproteinsthatassembleincellmembranesas tetramers[4,5]. Each monomer is
30 kDa and has sixmembrane-spanning domains surrounding a water porethat can transport water in both directions (Figure 1). AQPs selectively pass water, except for the aquaglycero-porins (AQP3, AQP7, AQP9), which also pass glycerol andsomepolar molecules.Mostofourknowledgeoftherolesof AQPs in different tissues comes from experiments with AQP-null mice (reviewed in Ref.). In general, AQPsincreasewaterpermeabilityacrossepithelia,thusallowing fast water ﬂow to accompany active salt transport. Thisprinciple is illustrated by AQP5 deletion in mice, whichcauses the salivary and airway submucosal glands tosecrete a low volume of relatively hypertonic ﬂuid[6,7]. AQPs also facilitate water ﬂow in response to passiveosmotic gradients. For example, AQPs increase osmoticreabsorption of water from renal collecting ducts and, as aresult, AQP-deﬁcient mice (AQPs 2–4) have impaired abil-ity to concentrate urine.Severalaquaglyceroporinfunctionshavebeendescribed,relatedtotheirglycerol-transportingability.Inhumansandrodents, AQP3 is found in skin keratinocytes. AQP3-nullmice have a dry, scaly skin because of reduced glycerolcontent in the stratum corneum and epidermis[9,10]. AQP7isexpressedinfatcells,andmicelackingAQP7carry more fat than wild-type mice. Because cell membraneglycerol permeability of AQP7-deﬁcient fat cells is reduced,glycerol accumulates intracellularly and stimulates trigly-ceride synthesis.
AQP expression in brain
AQP4, the principal AQP in mammalian brain, was ﬁrstcloned from rat lung and was found in electrically excitable tissues including brain, spinal cord, retina, innerear and skeletal muscle[12–18]. A general paradigm isthat AQP4 is not expressed in excitable cells, but is foundinsupportingcells(astrocytesandependymainthecentralnervous system [CNS]; Mu¨ller glia in the retina; Hensen’s,Claudius and inner sulcus cells in the ear). Brain AQP4 isstrongly expressed at the borders between brain parench-ymaandmajorﬂuidcompartmentsincludingastrocytefootprocesses(brain–blood),glialimitans(brain–subarachnoidcerebrospinal ﬂuid [CSF]), as well as ependymal cells and
TRENDS in Neurosciences
: Intracellular protein that may bind AQP4 and Kir4.1.
: Found in choroid plexus epithelium.
: Found in astrocyte foot processes, glia limitans, ependyma andsubependymal astrocytes.
: Found in some glia and neurons.
: Infiltrating astrocyte tumour, histologically graded I–IV.
Glia limitans externa
: Astrocyte processes bordering brain and subarachnoidCSF.
Glia limitans interna
: Astrocyte processes and ependyma bordering brain andventricular CSF.
: Inward rectifying K
channel that colocalizes with AQP4.
: A sheet-likecytoplasmic extension producedby migrating cells.
: AQP4 isoforms.
: Autoimmune disease characterized by optic neuritis andmyelitis.
: Excess water accumulation in tissue (see Box 1).
: Square lattice arrangement of AQP4 tetramers in cellmembrane.
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