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PMID:18234883

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Citation

Alessandri-Haber, N, Dina, OA, Joseph, EK, Reichling, DB and Levine, JD (2008) Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J. Neurosci. 28:1046-57

Abstract

Although the transient receptor potential vanilloid 4 (TRPV4) has been implicated in the process of osmomechanical transduction, it appears to make little contribution to the normal somatosensory detection of mechanical stimuli. However, evidence suggests that it may play an important role in mechanical hyperalgesia. In the present study, we examined the common requirement for TRPV4 in mechanical hyperalgesia associated with diverse pain models and investigated whether the very close association observed between TRPV4 and mechanical hyperalgesia, regardless of etiology, reflects a close functional connection of TRPV4 with other molecules implicated in mechanical transduction. In models of painful peripheral neuropathy associated with vincristine chemotherapy, alcoholism, diabetes, and human immunodeficiency virus/acquired immune deficiency syndrome therapy, mechanical hyperalgesia was markedly reduced by spinal intrathecal administration of oligodeoxynucleotides antisense to TRPV4. Similarly, mechanical hyperalgesia induced by paclitaxel, vincristine, or diabetes was strongly reduced in TRPV4 knock-out mice. We also show that alpha2beta1 integrin and Src tyrosine kinase, which have been implicated in mechanical transduction, are important for the development of mechanical hyperalgesia, and that their contribution requires TRPV4. Furthermore, we establish a direct interaction between TRPV4, alpha2 integrin, and the Src tyrosine kinase Lyn in sensory neurons. We suggest that TRPV4 plays a role in mechanotransduction, as a component of a molecular complex that functions only in the setting of inflammation or nerve injury.

Links

PubMed Online version:10.1523/JNEUROSCI.4497-07.2008

Keywords

Animals; Cells, Cultured; Hyperalgesia/genetics; Hyperalgesia/metabolism; Inflammation Mediators/metabolism; Integrin alpha2/genetics; Integrin alpha2/metabolism; Integrin alpha2beta1/genetics; Integrin alpha2beta1/metabolism; Integrins/genetics; Integrins/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nociceptors/metabolism; Pain Measurement/methods; Physical Stimulation/methods; Rats; Rats, Sprague-Dawley; TRPV Cation Channels/genetics; TRPV Cation Channels/metabolism; src-Family Kinases/genetics; src-Family Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:A0A0G2K470

enables

GO:0044877: protein-containing complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:A0A0G2K470

involved_in

GO:0050729: positive regulation of inflammatory response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:A0A0G2K470

involved_in

GO:0050966: detection of mechanical stimulus involved in sensory perception of pain

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:A0A0G2K470

involved_in

GO:0006971: hypotonic response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:LYN

part_of

GO:0034666: integrin alpha2-beta1 complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:LYN

enables

GO:0044877: protein-containing complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

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