title: Aggregation state determines the localization and function of M1- and M23-aquaporin-4 in astrocytes.
abstract: The astrocyte water channel aquaporin-4 (AQP4) is expressed as heterotetramers of M1 and M23 isoforms in which the presence of M23-AQP4 promotes formation of large macromolecular aggregates termed orthogonal arrays. Here, we demonstrate that the AQP4 aggregation state determines its subcellular localization and cellular functions. Individually expressed M1-AQP4 was freely mobile in the plasma membrane and could diffuse into rapidly extending lamellipodial regions to support cell migration. In contrast, M23-AQP4 formed large arrays that did not diffuse rapidly enough to enter lamellipodia and instead stably bound adhesion complexes and polarized to astrocyte end-feet in vivo. Co-expressed M1- and M23-AQP4 formed aggregates of variable size that segregated due to diffusional sieving of small, mobile M1-AQP4-enriched arrays into lamellipodia and preferential interaction of large, M23-AQP4-enriched arrays with the extracellular matrix. Our results therefore demonstrate an aggregation state-dependent mechanism for segregation of plasma membrane protein complexes that confers specific functional roles to M1- and M23-AQP4.
authors: Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, CA 94143.
authors: Alex J
authors: AJ
authors: Smith
authors: Byung-Ju
authors: BJ
authors: Jin
authors: Julien
authors: J
authors: Ratelade
authors: Alan S
authors: AS
authors: Verkman
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000502:physiology*; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D051379:Mice; D018345:Mice, Knockout; D008962:Models, Theoretical; D020033:Protein Isoforms; D055503:Protein Multimerization; D011554:Pseudopodia / Q000378:metabolism*; D045663:Quantum Dots
chemical_list: D051401:Aquaporin 4; D020033:Protein Isoforms