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 (IP₃) to produce inositol 1,3,4,5-tetrakisphosphate (IP₄) via the action of IP₃ 3-kinases involve the control of calcium signals. Using green fluorescent protein constructs of full-length and truncated IP₃ 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 α-helix. We also localized endogenous IP₃ 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 IP₃ in dendritic spines to produce IP₄ is likely to be important for modulating the compartmentalization of calcium at synapses.