Yun Wang’s group has recently published a paper on Science Signaling titled “Cdk5 inhibits the clathrin-dependent internalization of TRPV1 by phosphorylating the clathrin adaptor protein AP2μ2” and provides a detailed mechanism of TRPV1 internalization and a new potential target for clinical analgesic treatment (Liu et al., Sci. Signal. 2019).

Transient receptor potential vanilloid 1 (TRPV1), which is highly abundant on medium- and small-diameter nociceptive neurons, is a nonselective, ligand-gated cation channel that contributes to the development of diverse types of pain such as inflammatory pain, bone cancer pain, migraine, irritable bowel syndrome, and arthritis. TRPV1 also plays important roles in many other physiological and pathological processes such as itch, metabolic decline, autoimmune diabetes, pancreatitis, and modulation of vascular function.

TRPV1 is targeted by many kinases that influence its trafficking and activity. Studies on the internalization of TRPV1 have mainly focused on that induced by capsaicin or other agonists. Yun Wang’s group showed that constitutive internalization of TRPV1 occurred in a manner dependent on clathrin, dynamin, and adaptor protein complex 2 (AP2). The μ2 subunit of AP2 (AP2μ2) interacted directly with TRPV1 and was required for its constitutive internalization. Cyclin-dependent kinase 5 (CDK5) phosphorylated AP2μ2 at Ser45, which reduced the interaction between TRPV1 and AP2μ2, leading to decreased TRPV1 internalization. Intrathecal delivery of a cell-penetrating fusion peptide corresponding to the Cdk5 phosphorylation site in AP2μ2, which competed with AP2μ2 for phosphorylation by Cdk5, increased the abundance of TRPV1 on the surface of dorsal root ganglion neurons and reduced complete Freund’s adjuvant (CFA)-induced inflammatory thermal hyperalgesia in rats.

Working model：

In addition to describing a mechanism of TRPV1 constitutive internalization and its inhibition by CDK5, these findings demonstrate that CDK5 promotes inflammatory thermal hyperalgesia by reducing TRPV1 internalization, providing previously unidentified insights into the search for drug targets to treat pain.

This work was supported by grants from the National Natural Science Foundation of China and the National Key Technology Support Program of the Ministry of Science and Technology of China.

J. Liu, J. Du, Y. Wang, CDK5 inhibits the clathrin-dependent internalization of TRPV1 by phosphorylating the clathrin adaptor protein AP2μ2. Sci. Signal. 12, eaaw2040 (2019).