Figure 8.

Schematic model representing Cdk5-mediated motor–cargo association (A) and Cdk5 activity-regulated TRPV1 membrane trafficking (B, C). A, Cdk5-mediated phosphorylation of KIF13B at Thr-506 is necessary for the KIF13B–TRPV1 association. Other Cdk5-dependent phospho-regulated mechanisms may also be required. Whether KIF13B binds to a TRPV1-carrying vesicle via adaptor proteins is unknown. B, Under normal conditions, basal Cdk5 activity in nociceptive neurons is low, and only a few TRPV1-carrying vesicles are loaded and transported by phosphorylated KIF13B from the Golgi apparatus to the neuronal surface, maintaining a low surface level for normal sensitivity to noxious heat. C, After peripheral inflammation, Cdk5 activity is greatly elevated, and more TRPV1-carrying vesicles are loaded onto the motor and delivered to the cell surface. As a result, the number of TRPV1s at the neuronal surface (the plasma membrane of the soma and the peripheral axon) increases, contributing to the development and possibly the maintenance of heat hyperalgesia. If, at this time, the activated Cdk5-induced phosphorylation of KIF13B is disrupted by TAT–T506 peptide, the increase in TRPV1 membrane trafficking is prevented and the heat hyperalgesia is relieved to some extent.