Recent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD), where its role and mechanism of action remain unknown. We have previously established that the membrane receptor FGFR2 drives LUAD progression through aberrant protein–protein interactions mediated via its C-terminal proline-rich motif. Here we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline-rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2, hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p.
Recent evidence suggests ghrelin may up-regulate the number of spine synapses. However, it is not completely understood whether an increased number of synapses are expressed on existing spines or accommodated in newly generated spines. We examined if ghrelin might have promoted the generation of new dendritic spines. Localization of polymerized actin (F-actin), highly expressed in dendritic spines, was assayed using phalloidin, a mushroom toxin that has a high affinity to F-actin. Alexa 488-conjugated phalloidin was visualized and relative changes in fluorescing puncta were quantified using a confocal microscope. Ghrelin was applied to cultured hippocampal slices for either 60 min or 23 h. Ghrelin increased the phalloidin fluorescent signals. The antagonist of the ghrelin receptor, D-Lys3-GHSR-6, blocked the ghrelin’s effect of increasing the phalloidin signal, suggesting that the ghrelin’s effect was mediated by the ghrelin receptor (GHSR1a). The ghrelin-mediated increase in phalloidin signals remained elevated while ghrelin was present in the culture media for 23 h. However, removal of ghrelin from culture media restored the phalloidin signal to control level. Our results suggest ghrelin may have a stimulating effect on the generation or remodeling of dendritic spines, and the spine change persists in the presence of ghrelin. The serum ghrelin level is high when the stomach is empty, and the ghrelin level remains high until metabolic demands are fulfilled. Thus, ghrelin may be involved in food-related and appetite-related learning in the hippocampus.
Ghrelin and its receptor GHSR1a have been shown to exert numerous physiological functions in the brain, in addition to the well-established orexigenic role in the hypothalamus. Earlier work indicated that ghrelin stimulated the phosphorylation of the GluN1 subunit of the NMDA receptor (NMDAR) and enhanced synaptic transmission in the hippocampus. In the present study, we report that the exogenous application of ghrelin increased GluN2B phosphorylation. This increase was independent of GluN2B subunit activity or NMDAR channel activity. However, it depended on the activation of GHSR1a and Fyn as it was blocked by D-Lys3-GHRP-6 and PP2, respectively. Inhibitors for G-protein-regulated second messengers, such as Rp-cAMP, H89, TBB, ryanodine, and thapsigargin, unexpectedly enhanced GluN2B phosphorylation, suggesting that cAMP, PKA, casein kinase II, and cytosolic calcium signaling may oppose to the effect of ghrelin on the phosphorylation of GluN2B. Our findings suggest that 1) GluN2B is likely a molecular target of ghrelin and GHSR1a-driven signaling cascades, and 2) the ghrelin-mediated phosphorylation of GluN2B depends on Fyn activation under complex negative regulation by other second messengers.
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