Inositol 1,4,5-trisphosphate 3-kinase A is a novel microtubule-associated protein: PKA-dependent phosphoregulation of microtubule binding affinity

Inositol 1,4,5-trisphosphate 3-kinase A (IP₃K-A) is a brain specific and F-actin-binding protein. Werecently demonstrated that IP ₃K-A modulates a structural reorganization of dendritic spines through F-actin remodeling, which is required for synaptic plasticity and memory formation in brain. However, detailed functions of IP₃K-A and its regulatory mechanisms involved in the neuronal cytoskeletal dynamics still remain unknown. In the present study, we identified tubulin as a candidate of IP₃K-A-binding protein through proteomic screening. By various in vitro and in vivo approaches, we demonstrated that IP₃K-A was a novel microtubule-associated protein (MAP), and the N terminus of IP₃K-A was a critical region for direct binding to tubulin in dendritic shaft of hippocampal neurons. Moreover, PKA phosphorylated Ser-119 within IP ₃K-A, leading to a significant reduction of microtubule binding affinity. These results suggest that PKA-dependent phosphorylation and microtubule binding of IP₃K-A are involved in its regulatory mechanism for activity-dependent neuronal events such as local calcium signaling and its synaptic targeting.