Interaction of Transient Receptor Potential Vanilloid 4, Integrin, and Src Tyrosine Kinase in Mechanical Hyperalgesia

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 ␣2␤1 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, ␣2 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.

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…By both genetic and pharmacological approaches, we showed that TRPA1 entirely mediates mechanical and cold hypersensitivity induced by oxaliplatin and cisplatin [146] in mice and rats. We confirmed [103] that TRPV4 mediates part of the mechanical hyperalgesia induced by paclitaxel [74], and we showed that TRPV4-resistant mechanical hyperalgesia was exclusively mediated by TRPA1 [103]. We also discovered that paclitaxel-induced cold allodynia was completely due to TRPA1 activation [103].…”

“…Notwithstanding, recent evidence has emphasized a primary role for members of the TRP family, in particular TRPV1, TRPV4, TRPA1, and TRPM8, in the mechanical and thermal hypersensitivity evoked by chemotherapeutic agents in rodents [62,74,75].…”

“…In different models of painful peripheral neuropathy, mechanical hyperalgesia was markedly reduced by spinal intrathecal administration of oligodeoxynucleotides antisense to TRPV4 [74]. TRPV4 knock-out mice showed reduced mechanical hyperalgesia induced by the anticancer drugs, paclitaxel and vincristine, or in a diabetic model [74]. TRPV4 plays a major role in mechanical hyperalgesia, and also contributes to enhanced nociception to hypo-osmotic stimuli in paclitaxeltreated rats.…”

“…TRPV4-mediated hypersensitivity by paclitaxel is not attributable to increased mRNA levels, but rather it may be related to a specific interaction with second messenger pathways [101]. Similarly to paclitaxel, treatment with vincristine has been reported to produce mechanical allodynia in rodents through a TRPV4-dependent mechanism [74]. Authors suggest that TRPV4 is not directly activated by these agents, but plays a role in mechanotransduction, as a component of a molecular complex that functions only in presence of inflammation or nerve injury phenomena.…”

IP3 Receptor Binds to and Sensitizes TRPV4 Channel to Osmotic Stimuli via a Calmodulin-binding Site

“…TRPV4 participation in osmo-and mechanotransduction (1, 2) contributes to important functions including cellular (3, 4) and systemic volume homeostasis (5, 6), arterial dilation (7,8), nociception (9), epithelial hydroelectrolyte transport (10, 11), bladder voiding (12), and ciliary beat frequency regulation (13)(14)(15). TRPV4 also responds to temperature (16,17), endogenous arachidonic acid (AA) metabolites (18), and phorbol esters including the inactive 4␣-phorbol 12,13-didecanoate (4␣PDD) (19,20) and participates in receptor-operated Ca 2ϩ entry (15), thus showing multiple modes of activation.TRPV4 channel activity can be sensitized by co-application of different stimuli (9,21,22) or participation of different cell signaling pathways (14), suggesting the presence of different regulatory sites. In this sense, several proteins have been proposed to modulate TRPV4 subcellular localization and/or function: microtubuleassociated protein 7 (23), calmodulin (CaM, (24)), with no lysine protein kinases (25), and PACSIN3 (26).…”