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 Smith et al.
CITATION STYLE
Smith, A. J., Jin, B. J., Ratelade, J., & Verkman, A. S. (2014). Aggregation state determines the localization and function of M1- and M23-aquaporin-4 in astrocytes. Journal of Cell Biology, 204(4), 559–573. https://doi.org/10.1083/jcb.201308118
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