Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: EC:2.3.1.108 (
TAT
)
2,389
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cyclin-dependent kinase 5 (Cdk5) is an important serine/threonine kinase that plays critical roles in many physiological processes. Recently, Cdk5 has been reported to phosphorylate
TRPV1
at threonine 407 (Thr-407) in humans (Thr-406 in rats), which enhances the function of
TRPV1
channel and promotes thermal hyperalgesia in the complete Freund's adjuvant (CFA)-induced inflammatory pain rats. However, the underlying mechanisms are still unknown. Here, we demonstrate that Cdk5 phosphorylates
TRPV1
at Threonine 406 and promotes the surface localization of
TRPV1
, leading to inflammatory thermal hyperalgesia. The mutation of Thr-406 of
TRPV1
to alanine reduced the interaction of
TRPV1
with the cytoskeletal elements and decreased the binding of
TRPV1
with the motor protein KIF13B, which led to reduced surface distribution of
TRPV1
. Disrupting the phosphorylation of
TRPV1
at Thr-406 dramatically reduced the surface level of
TRPV1
in HEK 293 cells after transient expression and the channel function in cultured dorsal root ganglion (DRG) neurons. Notably, intrathecal administration of the interfering peptide against the phosphorylation of Thr-406 alleviated heat hyperalgesia and reduced the surface level of
TRPV1
in inflammatory pain rats. Together, these results demonstrate that Cdk5-mediated phosphorylation of
TRPV1
at Thr-406 increases the surface level and the function of
TRPV1
, while the
TAT
-T406 peptide can effectively attenuate thermal hyperalgesia. Our studies provide a potential therapy for inflammatory pain.
...
PMID:Phosphorylation of TRPV1 by cyclin-dependent kinase 5 promotes TRPV1 surface localization, leading to inflammatory thermal hyperalgesia. 2637 15
TRPV4 ion channels have a broad expression profile and were shown to contribute to enhanced pain sensation in inflammation. Directly blocking TRPV4 might run the risk of interfering with normal physiology, and has prompted to explore the interaction with the scaffolding protein AKAP79, an approach successfully used for
TRPV1
channels. HEK293t cells express AKAP79, additional transfection did not sensitize human TRPV4. Application of trypsin facilitated responses to TRPV4 agonist GSK1016790A. Using a specific protease-activated receptor 2 agonist, involvement of an A-kinase anchoring protein in TRPV4 activation was demonstrated by inhibition with AKAP inhibitor peptide Ht31. TRPV4 has substantial sequence similarity to
TRPV1
in the range interacting with AKAP79. A synthetic peptide, resembling these amino acids and extended by a positive region for transmembrane uptake, was tested. Sensitization of TRPV4 responses could be reduced after exposure to this 771-781::
TAT
peptide but not by a scrambled control peptide. This validates the concept of targeting the interaction between TRPV4 and AKAP79 and controlling increased TRPV4 activity.
...
PMID:Disrupting sensitization of TRPV4. 2837 87
