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Platelet-Derived Growth Factor
Published in Jason Kelley, Cytokines of the Lung, 2022
James P. Fabisiak, Jason Kelley
However, PDGF-AA and PDGF-BB may differentially stimulate specific second-messenger pathways (Sachinidis et al., 1990; Block et al., 1989). For example, PDGF-BB readily stimulates the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) along with changes in intracellular pH and Ca2+ in smooth-muscle cells. On the other hand, PDGF-AA selectively induces DAG formation independent of other changes. In addition, the time course of DAG formation in response to PDGF-AA differs significantly from that observed with the AB and BB isoforms.
Mitochondrial Dysfunction in Huntington Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Md. Hafiz Uddin, Marufa Rumman, Tasnuva Sarowar
As reported recently, there is a reduced calcium loading capacity in HD mitochondria (Pandey, Mohanakumar, and Usha 2010). Ca2+ signaling is crucial for managing the normal functioning of neurons. Calcium functions as a second messenger to modulate the activity of kinases, phosphatases, proteases, ion transporters and channels, neurotransmitters, and gene transcription. Thus, it is crucial to maintain Ca2+ concentrations below an optimal level (e.g., 100 nM) to keep neural activity uninterrupted. Different classes of ion channels mediate calcium influx, including voltage-gated calcium channels, glutamate-gated NMDA, and certain subtypes of AMPA receptors. In addition to endoplasmic reticulum (ER), mitochondria are one of the major intracellular stores for calcium and can release calcium depending on the physiological process. Intracellular calcium levels are maintained in low concentrations by sequestration in the mitochondrial matrix and ER (Raymond 2017).
Synapses
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Second messengers are molecules that relay signals from postsynaptic receptors activated by extracellular substances, termed first messengers, to molecules inside the cell, which in turn affect cell activity in some way. Second messengers are involved in a variety of cell functions, including hormone activity and gating of ion channels, where the first messengers are hormones and neurotransmitters, respectively. Some substances can act both as neurotransmitters, when released from presynaptic terminals, and as hormones, when secreted by specialized organs into the blood stream. Examples are epinephrine, norepinephrine, serotonin, and dopamine.
Protective effects of vitamin D3 (cholecalciferol) on vancomycin-induced oxidative nephrotoxic damage in rats
Published in Pharmaceutical Biology, 2023
Rouba Yasser Al-Sroji, Shaza Al-Laham, Ahmad Almandili
The majority of vitamin D3 in the body is obtained through sunlight-initiated biosynthesis in the skin. When the skin is exposed to UVB radiation and thermal stimulation, a7-dehydrocholesterol is converted to pre-vitamin D3 and then to vitamin D3 (Zella and DeLuca 2003). First, vitamin D3 is converted to 25(OH)D in the liver by hydroxylation; then the second hydroxylation occurs in the kidneys, which produces 1,25(OH)2D3, which is the biologically active form of vitamin D3. It binds to the nuclear vitamin D receptor (VDR) or the plasma membrane VDR. The biological actions of 1,25 (OH)2D3 mediate control gene expression (Deluca and Cantorna 2001; Zella and DeLuca 2003). VitD3-VDR forms homodimers or heterodimers with the retinoid X receptor (RXR), then the homodimers or heterodimers bind to vitamin D3 response elements (VDRE). Thus, the expression of specific target genes is activated (Dulak et al. 2000). The VDR mediates both genomic and non-genomic actions of vitamin D3. These two kinds of actions are involved in physiological processes through regulating the transcriptional activity of target genes and activation of intracellular second messengers, respectively (Feghali and Wright 1997; Donato et al. 2009).
Hyperoside ameliorates cerebral ischaemic–reperfusion injury by opening the TRPV4 channel in vivo through the IP3-PKC signalling pathway
Published in Pharmaceutical Biology, 2023
Lei Shi, Chenchen Jiang, Hanghang Xu, Jiangping Wu, Jiajun Lu, Yuxiang He, Xiuyun Yin, Zhuo Chen, Di Cao, Xuebin Shen, Xuefeng Hou, Jun Han
Accumulating evidence has shown that TRPV4 activation influences vascular dilation by inducing the production of EDHF, NO or PGI2 (Liu et al. 2021). Similar to previous studies, we also found that Hyp-induced vasodilatation is dependent on EDHF production in an NO- and PGI2-independent manner in endothelial cells from the CBA of IR rats. To further investigate the mechanism by which Hyp affects TRPV4 expression, we focused on IP3 and PKC. IP3-associated and PKC-mediated signalling pathways play a critical role in inducing PGI2- and NO-independent vasodilation. IP3 is an important second messenger that binds to inositol triphosphate receptors on the sarcoplasmic reticulum to cause Ca2+ release and an increase in intracellular Ca2+ concentration (Ivanova et al. 2017). Studies have shown that IP3 activation promotes the opening of TRPV4 channels (Heathcote et al. 2019). PKC induces vasodilation through the EDHF mechanism by activating TRPV4, which plays an important role in regulating vasomotor function (Sonkusare et al. 2014). The results herein showed that the expression of IP3R and PKC was markedly increased by the Hyp treatment, and this effect was reduced by treatment with an IP3R inhibitor (2APB) or an inhibitor of PKC (BisI). Importantly, the effect of Hyp on TRPV4 expression was considerably suppressed by the 2APB and BisI treatment, suggesting that Hyp upregulates TRPV4 expression through the activation of the IP3 and PKC signalling pathways.
Bruton’s tyrosine kinase as a promising therapeutic target for multiple sclerosis
Published in Expert Opinion on Therapeutic Targets, 2023
Darius Saberi, Anastasia Geladaris, Sarah Dybowski, Martin S. Weber
After antigen binding to the B cell receptor (BCR), Lck/Yes novel tyrosine kinase (Lyn), a member of the SRC kinase family phosphorylates the Igα and Igβ immunoreceptor tyrosine-based activation motifs (ITAMs), which then binds spleen tyrosine kinase (SYK). In the next step, SYK gets phosphorylated by Lyn and BTK is recruited from the cytosol to the plasma membrane [75]. In general, activation of BTK is characterized by phosphorylation at the position Y551 of BTK. This promotes the catalytic activity of BTK and subsequently results in its autophosphorylation at the position Y223 in its SH3 domain [71]. Active BTK phosphorylates phospholipase C gamma 2 (PLCγ2). Consequently, PLCγ2 generates two second messengers, inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The activation of calcium channels by IP3 results in a transport of nuclear factor of activated T cells (NFAT) into the nucleus. The pathway of nuclear factor ‘kappa-light-chain-enhancer’ (NF-κB) of activated B cells and mitogen-associated protein kinase (MAPK) is activated by DAG. The expression of several genes that are essential for B cell survival and proliferation chemokine and cytokine expression is regulated by NFAT and NF-κB (Figure 1). In summary, this complex cascade leads to an increase in survival and accelerates the proliferation of B cells, and therefore highlights the pivotal role of BTK in B cells [76].