Research ArticlePain

CDK5 inhibits the clathrin-dependent internalization of TRPV1 by phosphorylating the clathrin adaptor protein AP2μ2

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Science Signaling  11 Jun 2019:
Vol. 12, Issue 585, eaaw2040
DOI: 10.1126/scisignal.aaw2040

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Constitutive internalization of a nociceptor

The nonselective cation channel TRPV1 elicits the sensation of burning pain in response to thermal or chemical stimuli and contributes to inflammatory thermal hyperalgesia, the increased sensitivity of inflamed tissues to heat. Liu et al. found that TRPV1 was constitutively internalized in cultured human cells and rat neurons through clathrin-mediated endocytosis. TRPV1 internalization depended on binding to the clathrin adaptor protein complex 2 subunit μ2 (AP2μ2) and was antagonized by phosphorylation of AP2μ2 by cyclin-dependent kinase 5 (CDK5). Treating rats with a peptide that interfered with Cdk5-mediated AP2μ2 phosphorylation reduced inflammatory thermal hyperalgesia, suggesting that strategies for promoting TRPV1 internalization might lead to effective treatments for pain.

Abstract

Transient receptor potential vanilloid 1 (TRPV1), a nonselective, ligand-gated cation channel, responds to multiple noxious stimuli and 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. Here, we report 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. 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.

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