biostudies-literatureSmith AJNIBIB NIH HHSNEI NIH HHSNIDDK NIH HHS559-73https://www.ebi.ac.uk/biostudies/studies/S-EPMC3926963biostudies-literatureUnknown204(4)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.The Journal of cell biologyAggregation state determines the localization and function of M1- and M23-aquaporin-4 in astrocytes.PMC3926963DK35124R01 EY013574EB00415R37 EB000415RC1 DK086125R01 EB000415DK72517P30 DK072517EY13574R37 DK035124R01 DK035124DK86125Ratelade JVerkman ASJin BJSmith AJfalseAggregation state determines the localization and function of M1- and M23-aquaporin-4 in astrocytes.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-AQP4.2014-01-01T00:00:00Z2014 Feb2022-02-09T10:30:01.424Z2019-03-27T01:21:55ZS-EPMC39269632451534910.1083/jcb.201308118