α-Tubulin Acetylation Restricts Axon Overbranching by Dampening Microtubule Plus-End Dynamics in Neurons.

Axon growth is tightly controlled to establish functional neural circuits during brain development. Despite the belief that cytoskeletal dynamics is critical for cell morphology, how microtubule acetylation regulates axon development in the mammalian central nervous system remains unclear. Here, we report that loss of α-tubulin acetylation by ablation of MEC-17 in mice predisposes neurons to axon overbranching and overgrowth. Introduction of MEC-17F183A lacking α-tubulin acetyltransferase activity into MEC-17-deficient neurons failed to rescue axon defects. Moreover, loss of α-tubulin acetylation led to increases in microtubule debundling, microtubule invasion into filopodia and growth cones, and microtubule plus-end dynamics along the axon. Taxol application dampened microtubule hyperdynamics and suppressed axon overbranching and overgrowth in MEC-17-deficient neurons. Thus, our study reveals that α-tubulin acetylation acts as a brake for axon overbranching and overgrowth by dampening microtubule dynamics, providing insight into the role of microtubule post-translational modifications in regulating neural development.

CaMKIIα and caveolin-1 cooperate to drive ATP-induced membrane delivery of the P2X3 receptor.

The P2X3 receptor plays a vital role in sensory processing and transmission. The assembly and trafficking of the P2X3 receptor are important for its function in primary sensory neurons. As an important inflammation mediator, ATP is released from different cell types around primary sensory neurons, especially under pathological pain conditions. Here, we show that α, ß-MeATP dramatically promoted membrane delivery of the P2X3 receptor both in HEK293T cells expressing recombinant P2X3 receptor and in rat primary sensory neurons. α, ß-MeATP induced P2X3 receptor-mediated Ca²âº influx, which further activated Ca²âº/calmodulin-dependent protein kinase IIα (CaMKIIα). The N terminus of the P2X3 receptor was responsible for CaMKIIα binding, whereas Thr³88 in the C terminus was phosphorylated by CaMKIIα. Thr³88 phosphorylation increased P2X3 receptor binding to caveolin-1. Caveolin-1 knockdown abrogated the α, ß-MeATP-induced membrane insertion of the P2X3 receptor. Moreover, α, ß-MeATP drove the CaMKIIα-mediated membrane coinsertion of the P2X2 receptor with the P2X3 receptor. The increased P2X3 receptors on the cell membrane that are due to Thr³88 phosphorylation facilitated P2X3 receptor-mediated signal transduction. Together, our data indicate that CaMKIIα and caveolin-1 cooperate to drive ligand-induced membrane delivery of the P2X3 receptor and may provide a mechanism of P2X3 receptor sensitization in pain development.