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J. Cell Biol. 194 (6): 905-920

Copyright © 2011 by the Rockefeller University Press.

Article

GRK5 promotes F-actin bundling and targets bundles to membrane structures to control neuronal morphogenesis

Yuejun Chen1,2, Feifei Wang1,2, Hui Long1,2, Ying Chen1,2, Ziyan Wu1,2, , and Lan Ma1,2

1 The State Key Laboratory of Medical Neurobiology and 2 Pharmacology Research Center, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China

Correspondence to Lan Ma: lanma{at}shmu.edu.cn

Abstract: Neuronal morphogenesis requires extensive membrane remodeling and cytoskeleton dynamics. In this paper, we show that GRK5, a G protein–coupled receptor kinase, is critically involved in neurite outgrowth, dendrite branching, and spine morphogenesis through promotion of filopodial protrusion. Interestingly, GRK5 is not acting as a kinase but rather provides a key link between the plasma membrane and the actin cytoskeleton. GRK5 promoted filamentous actin (F-actin) bundling at the membranes of dynamic neuronal structures by interacting with both F-actin and phosphatidylinositol-4,5-bisphosphate. Moreover, separate domains of GRK5 mediated the coupling of actin cytoskeleton dynamics and membrane remodeling and were required for its effects on neuronal morphogenesis. Accordingly, GRK5 knockout mice exhibited immature spine morphology and deficient learning and memory. Our findings identify GRK5 as a critical mediator of dendritic development and suggest that coordinated actin cytoskeleton and membrane remodeling mediated by bifunctional actin-bundling and membrane-targeting molecules, such as GRK5, is crucial for proper neuronal morphogenesis and the establishment of functional neuronal circuitry.

Abbreviations: ANOVA, analysis of variance • BK, bradykinin • DIV, day in vitro • EmGFP, Emerald GFP • G-actin, globular actin • GPCR, G protein–coupled receptor • GRK, GPCR kinase • KO, knockout • miRNA, microRNA • PAO, phenylarsine oxide • PC, phosphatidylcholine • PI(4, 5)P2, phosphatidylinositol-4,5-bisphosphate • TDBTN, total dendritic branch tip number • WT, wild type

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