GRK5 Goes Neuronal

Science Signaling  27 Sep 2011:
Vol. 4, Issue 192, pp. ec270
DOI: 10.1126/scisignal.4192ec270

Appropriate neuronal morphology is important for functional neural circuitry, whereas altered neuronal morphology is associated with various cognitive disorders. Proper morphogenesis of neurites and dendritic spines requires dynamic remodeling of the actin cytoskeleton and the cell membrane. Chen et al. demonstrated that G protein–coupled receptor kinase 5 (GRK5) promoted neuronal morphogenesis by linking actin bundles with phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that interacts with actin regulatory proteins to transmit signals from the cell membrane to the cytoskeleton. Both wild-type and kinase-dead GRK5 associated with and bundled actin filaments in vitro, and this activity required a short sequence in the C-terminal region of GRK5 in which five residues were basic amino acids (lysine or arginine). GRK5 also linked actin bundles to PIP2-enriched liposomes but not to liposomes enriched with phosphatidylcholine. In contrast to GRK5’s actin-bundling activity, binding to PIP2 was mediated by basic amino acids in the N-terminal region of GRK5. Endogenous and HA-tagged GRK5 colocalized with actin in dendritic spines of cultured hippocampal neurons. Furthermore, cultured hippocampal neurons overexpressing either wild-type or kinase-dead GRK5, but not a GRK5 C-terminal mutant defective in actin binding, exhibited an increase in both total dendrite length and dendritic spine density in comparison with control neurons. Western blotting revealed an increase in GRK5 protein abundance in the hippocampus and cortex of the developing rat brain during dendritic development. Conversely, hippocampal neurons from GRK5 knockout mice showed a reduction in neurite number, neurite length, and the density of mature dendritic spines compared with wild-type mice. GRK5 knockout mice also performed poorer than wild-type mice on learning and memory tests. Together, the results suggest a kinase-independent scaffolding function for GRK5 in promoting neuronal morphogenesis.

Y. Chen, F. Wang, H. Long, Y. Chen, Z. Wu, L. Ma, GRK5 promotes F-actin bundling and targets bundles to membrane structures to control neuronal morphogenesis. J. Cell Biol. 194, 905–920 (2011). [Abstract] [Full Text]