| Summary: | 碩士 === 國立中央大學 === 生命科學研究所 === 100 === High local proton concentrations (tissue acidosis) found in some chronic inflammation complaints cause painfulness. The degree of associated pain is well correlated with magnitude of acidification. This is attributable to direct excitation of nociceptive sensory neurons or indirect modulation by proton-sensing receptors. Transient receptor potential vanilloid 1 (TRPV1), a proton-sensing ion channel, is involved in inflammatory pain because TRPV1 gene expression is increased and its function is enhanced in inflamed dorsal root ganglion (DRG) neurons. It is recently found that a proton-sensing G-protein-coupled receptors, TDAG8, has increased expression in inflamed DRG and its activation can enhance TRPV1 function. However, it remains unclear how TDAG8 activation sensitizes TRPV1 function. This thesis is to elucidate (1) the mechanism of TDAG8-mediated TRPV1 sensitization, and (2) the acidification- and chronic inflammation-induced TRPV1 sensitization in DRG neurons.
I have demonstrated that TDAG8 responds proton to sensitize TRPV1 through PKA- and PKCε-dependent pathways. In TDAG8-expressing cells, TDAG8 can activate Gs protein and then activate PKA or PKCε to sensitize TRPV1. Interestingly, at pH <6.0, TDAG8 can also sensitize TRPV1 through PTX- and U73122-sensitive pathways. In cultured DRG neurons, mild acidification (pH 6.8) induced TRPV1 sensitization through PKA-dependent pathways in IB4-positive neurons, although acidification induced PKA and PKCε translocation. Further studies revealed that CFA-induced long-term inflammation leading to TRPV1 sensitization through PKCε-dependent pathway. Accordingly, PKA and PKCε are involved in TRPV1 sensitization based on different situations.
|
|---|
