Inositol 1,4,5-trisphosphate 3-kinase A associates with F-actin and dendritic spines via its N terminus.

The consequences of the rapid 3-phosphorylation of inositol 1,4,5-trisphosphate (IP(3)) to produce inositol 1,3,4,5-tetrakisphosphate (IP(4)) via the action of IP(3) 3-kinases involve the control of calcium signals. Using green fluorescent protein constructs of full-length and truncated IP(3) 3-kinase isoform A expressed in HeLa cells, COS-7 cells, and primary neuronal cultures, we have defined a novel N-terminal 66-amino acid F-actin-binding region that localizes the kinase to dendritic spines. The region is necessary and sufficient for binding F-actin and consists of a proline-rich stretch followed by a predicted alpha-helix. We also localized endogenous IP(3) 3-kinase A to the dendritic spines of pyramidal neurons in primary hippocampal cultures, where it is co-localized postsynaptically with calcium/calmodulin-dependent protein kinase II. Our experiments suggest a link between inositol phosphate metabolism, calcium signaling, and the actin cytoskeleton in dendritic spines. The phosphorylation of IP(3) in dendritic spines to produce IP(4) is likely to be important for modulating the compartmentalization of calcium at synapses.