Role of growth factor receptor transactivation in high glucose-induced increased levels of Gq/11α and signaling in vascular smooth muscle cells

We have recently shown that high glucose increased the expression of Gq/11α, PLCβ and mediated signaling in A10 vascular smooth muscle cells (VSMC). Since high glucose has been shown to increase growth factor receptor activation, we investigated the role of epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) transactivation in high glucose-induced enhanced expression of Gq/11α and PLCβ. Pre-treatment of A10 VSMC with high glucose (26 mM) for 3 days, increased the levels of Gqα, G11α, PLCβ-1 and PLCβ-2 proteins which were restored to control levels by AG1478, an inhibitor of EGF-R, AG1295, an inhibitor of PDGF-R and PP2, an inhibitor of c-Src but not by PP3. In addition, endothelin-1 (ET-1)-stimulated production of IP₃ that was enhanced by high glucose was also restored towards control levels by AG1478, AG1295 and PP2. High glucose also increased the phosphorylation of EGF-R and PDGF-R which was abolished by AG1478, AG1295 and PP2. Furthermore, high glucose-induced enhanced levels of Gqα, G11α and PLCβ were also attenuated by PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) and wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-K). In addition, AG1478 and AG1295, also attenuated high glucose-induced enhanced phosphorylation of ERK1/2 and AKT. Furthermore, high glucose augmented the phosphorylation of c-Src which was attenuated by antioxidant, DPI. These results suggest that oxidative stress through the activation of c-Src and resultant transactivation of growth factor receptor contributes to the high glucose-induced enhanced expression of Gq/11α/PLC and -mediated cell signaling through MAPK/PI3K pathway.     

Localization of phospholipid-related signal molecules in salivary glands of rodents: A review

BackgroundIn the 1950s, Hokin conducted initial studies on phosphoinositide turnover/cycle in salivary glandular cells. From these studies, the idea emerged that receptor-mediated changes in intramembranous levels of phosphoinositides represent an early step in the stimulus-response pathway. Based on this idea and the general view that knowledge of the exact localization of a given endogenous molecule in cells in situ is important for understanding its functional significance, we have reviewed available information about the localization of several representative phosphoinositide-signaling molecules in the salivary glands in situ in mice.HighlightWe focused on phosphatidylinositol 4-kinase, phosphatidylinositol 4 phosphate 5-kinase α, β, γ, phospholipase Cβ, muscarinic cholinoceptors 1 and 3, diacylglycerol kinase ζ, phospholipase D1 and 2, ADP-ribosylation factor 6 and its exchange factors for Arf6, and cannabinoid receptors. These molecules individually exhibit differential localization in a spatiotemporal manner in the exocrine glands, making it possible to deduce their functional significance, such as their involvement in secretion and cell differentiation.ConclusionAlthough phosphoinositide-signaling molecules whose in situ localization in glandular cells has been clarified are still limited, the obtained information on their localization suggests that their functional significance is more valuable in glandular ducts than in acini. It thus suggests the necessity of greater attention to the ducts in their physio-pharmacological analyses. The purpose of this review is to encourage more in situ localization studies of phosphoinositide-signaling molecules with an aim to further understand their possible involvement in the pathogenesis of salivary gland diseases.     

The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies

Transient receptor potential (TRP) channels are one primary type of calcium (Ca²⁺) permeable channels, and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems. Nowadays, however, accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression, inducing tumor invasion and metastasis. However, the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive. Therefore, in this review, we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, immune surveillance evasion, and the alterations of relevant tumor micro-environment. Moreover, we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors’ efficacy. The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented. Furthermore, it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.