Src Family Kinases in the Central Nervous System: Their Emerging Role in Pathophysiology of Migraine and Neuropathic Pain.
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ABSTRACT:
SUBMITTER: Nie L
PROVIDER: S-EPMC8573745 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neuropathic pain is a major clinic probelm as it is very difficult to treat and mechanism remain unknown. Here, we investigated the differential expression of proteins in the central nuecleus of amygdala (CeA) in neuropathic pain moldel spinal nerve transection (SNT)in rats. CeA was excised from naive, sham, SNTmodels at days 3, 7, 14 and 21 rats. The aim was to quatify the differential proteins in CeA including memebrane proteins. We used gel- and mass spectrometry- based proteomics. For gel-proteomics, total tissue lysate proteins were separated by 2D-PAGE. The 2D gels from different SNT time points against Sham and control rats were compared using Progenesis SameSpot software. The spots with fold change greater then 2 excised for the proteins IDs by LC-MS/MS. Protein spots were digested using trypsin. Extracted peptides were injected on the nano C18 column and measured by a LTQ Orbitrap XL or a LTQ Orbitrap Velos mass spectrometers. For the identification of membrane proteins in CeA, we used 1-SDS-PAGE and cut the gel region of MW 80 kDa and higher for nano-LC-MS/MS analysis. We also quantified membrane proteins by utilising triplex stabel isotope dimethyl labelling at the peptide level. Sham, control and day 3, 7 and 21 after SNT surgery rats CeA membrane proteins were purified and digested by trypsin and labelled with "light", "medium" and "heavy" dimethyl labelling reagents. The resulting peptides were analysed by a nano LC connected to the Q Exactive mass spectrometer. Quantification of peptide was processed using Proteome Discoverer 1.3.
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Project description:Cell adhesion molecules, including integrins, cadherins, and claudins (CLDNs), are known to activate Src-family kinases (SFKs) that organize a variety of physiological and pathological processes; however, the underlying molecular basis remains unclear. Here, we identify the SFK members that are coupled with the CLDN6-adhesion signaling. Among SFK subtypes, BLK, FGR, HCK, and SRC were highly expressed in F9 cells and concentrated with CLDN6 along cell borders during epithelial differentiation. Immunoprecipitation assay showed that BLK and SRC, but not FGR or HCK, form a complex with CLDN6 via the C-terminal cytoplasmic domain. We also demonstrated, by pull-down assay, that recombinant BLK and SRC proteins directly bind to the C-terminal cytoplasmic domain of CLDN6 (CLDN6C). Unexpectedly, both recombinant SFK proteins recognized the CLDN6C peptide in a phosphotyrosine-independent manner. Furthermore, by comparing phenotypes of F9:Cldn6:Blk-/- and F9:Cldn6:Src-/- cells with those of wild-type F9 and F9:Cldn6 cells, we revealed that BLK and SRC are essential for CLDN6-triggered cellular events, namely epithelial differentiation and the expression of retinoid acid receptor target genes. These results indicate that selective SFK members appear to participate in the CLDN-adhesion signaling.
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