title: Regulation of the perilymphatic-endolymphatic water shunt in the cochlea by membrane translocation of aquaporin-5.
abstract: Volume homeostasis of the cochlear endolymph depends on radial and longitudinal endolymph movements (LEMs). LEMs measured in vivo have been exclusively recognized under physiologically challenging conditions, such as experimentally induced alterations of perilymph osmolarity or endolymph volume. The regulatory mechanisms that adjust LEMs to the physiological requirements of endolymph volume homeostasis remain unknown. Here, we describe the formation of an aquaporin (AQP)-based "water shunt" during the postnatal development of the mouse cochlea and its regulation by different triggers. The final complementary expression pattern of AQP5 (apical membrane) and AQP4 (basolateral membrane) in outer sulcus cells (OSCs) of the cochlear apex is acquired at the onset of hearing function (postnatal day (p)8-p12). In vitro, hyperosmolar perfusion of the perilymphatic fluid spaces or the administration of the muscarinic agonist pilocarpine in cochlear explants (p14) induced the translocation of AQP5 channel proteins into the apical membranes of OSCs. AQP5 membrane translocation was blocked by the muscarinic antagonist atropine. The muscarinic M3 acetylcholine (ACh) receptor (M3R) was identified in murine OSCs via mRNA expression, immunolabeling, and in vitro binding studies using an M3R-specific fluorescent ligand. Finally, the water shunt elements AQP4, AQP5, and M3R were also demonstrated in OSCs of the human cochlea. The regulation of the AQP4/AQP5 water shunt in OSCs of the cochlear apex provides a molecular basis for regulated endolymphatic volume homeostasis. Moreover, its dysregulation or disruption may have pathophysiologic implications for clinical conditions related to endolymphatic hydrops, such as Ménière's disease.
authors.affiliation: Department of Otorhinolaryngology-Head & Neck Surgery, University of Tübingen Medical Centre, Tübingen, Germany.|Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Eckhard
authors.affiliation: Department of Otorhinolaryngology-Head & Neck Surgery, University of Tübingen Medical Centre, Tübingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dos Santos
authors.affiliation: Department of Surgical Sciences, Section of Otolaryngology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Otorhinolaryngology-Head & Neck Surgery, University of Tübingen Medical Centre, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bassiouni
authors.affiliation: Department of Otorhinolaryngology-Head & Neck Surgery, University of Tübingen Medical Centre, Tübingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Arnold
authors.affiliation: Institute of Anatomy, University of Tübingen, Tübingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Gleiser
authors.affiliation: Institute of Anatomy, University of Tübingen, Tübingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Hirt
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Interfaculty Center of Pharmacogenomics and Pharmaceutical Research (ICePhA), University of Tübingen, Tübingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Harteneck
authors.affiliation: School of Medicine and Health Sciences - European Medical School, University Hospital of Otorhinolaryngology, Medical Campus University of Oldenburg, Steinweg 13-17, 26122, Oldenburg, Germany.|Research Center of Neurosensory Science, University of Oldenburg, 26111, Oldenburg, Germany.|Cluster of Excellence Hearing4all, University of Oldenburg, 26111, Oldenburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Surgical Sciences, Section of Otolaryngology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Rask-Andersen
authors.affiliation: School of Medicine and Health Sciences - European Medical School, University Hospital of Otorhinolaryngology, Medical Campus University of Oldenburg, Steinweg 13-17, 26122, Oldenburg, Germany. hubert.loewenheim@uni-oldenburg.de.|Research Center of Neurosensory Science, University of Oldenburg, 26111, Oldenburg, Germany. hubert.loewenheim@uni-oldenburg.de.|Cluster of Excellence Hearing4all, University of Oldenburg, 26111, Oldenburg, Germany. hubert.loewenheim@uni-oldenburg.de.
authors.forename: H
authors.initials: H
authors.lastname: Löwenheim
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism; D051402:Aquaporin 5 / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D018678:Cholinergic Agents / Q000494:pharmacology; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism*; D004710:Endolymph / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D014867:Water / Q000378:metabolism
chemical_list: C496031:Aqp4 protein, mouse; C496038:Aqp5 protein, mouse; D051401:Aquaporin 4; D051402:Aquaporin 5; D018678:Cholinergic Agents; D043587:Receptor, Muscarinic M3; D014867:Water
keywords: Aquaporin; Cochlea; Muscarinic; Ménière’s disease; Pilocarpine; Water permeability