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Vascular smooth muscle: excitation, contraction and relaxation
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
SACs are mechano-dependent TRP channels that are activated by stretch of the vessel wall. They contribute to a contractile response of blood vessels to stretch, called the myogenic response, which is the basis of autoregulation (Sections 13.2 and 13.6). A variety of TRP channels have been implicated including TRPC6, TRP cation channel subfamily V member 2 and 4 and TRP cation channel subfamily M member 4.
Natural Products as an Effective Treatment Option for Depression
Published in Vikas Kumar, Addepalli Veeranjaneyulu, Herbs for Diabetes and Neurological Disease Management, 2018
Yogesh Anant Kulkarni, Kalyani Himanshu Barve, Ginpreet Kaur
Hyperforin, a prenylated phloroglucinol, isolated from the flowers of this plant is the most active form and has been reported to treat mild to moderate depression. The mechanisms of hyperforin actions are not yet understood, but may include inhibition of 5-lipoxygenase, high affinity binding to the pregnane X receptor, release of Ca2+ and/or Zn2+ from intracellular stores, and affecting of presynaptic and vesicular uptake, storage and release of neurotransmitters such as serotonin, dopamine, norepinephrine, acetylcholine, GABA, and glutamate. It is also believed that the activity is due to TRPC6 channel activation and hyperforin acts as a protonophore which causes cytosolic acidification, in turn activating the plasma membrane sodium-proton exchanger. Thereby the free intracellular sodium concentration increases and the neurotransmitter uptake by Na+ cotransport is inhibited. Additionally, hyperforin depletes and reduces loading of large dense core vesicles in chromaffin cells, which requires a pH gradient in order to accumulate monoamines.41
Herbs with Antidepressant Effects
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Hypericum perforatum appears to have multiple mechanisms of action in producing antidepressant effects. Hypericum perforatum, particularly hyperforin, inhibits neuronal uptake not only of serotonin and noradrenaline – the common mechanisms of action of standard antidepressant medications – but also of dopamine, gamma-aminobutyric acid, and l-glutamate. Moreover, hyperforin does not act as a competitive inhibitor at the transmitter binding sites of the transporter proteins, but rather it affects the sodium gradient that in turn leads to an inhibition of transmitter uptake.19 In a 2014 paper by Sell et al.,20 it was admitted that we still do not understand the mechanism of action of hyperforin, the primary antidepressant component of Hypericum perforatum. Among the possibilities noted were: inhibition of 5-lipoxygenase; high affinity binding to the pregnane X receptor; release of Ca2+ and/or Zn2+ from intracellular stores; as well as the prominent hypothesis of diminishing reuptake of serotonin, dopamine, norepinephrine, acetylcholine, GABA, and glutamate. An earlier study had purported to show that hyperforin reduces uptake of the variety of neurotransmitters through activation of the somewhat mysterious neuronal channel protein, TRPC6. The activation of TRPC6 by hyperforin was also said to induce neuronal axonal sprouting, such as would be seen after the addition of various nerve growth factors.21 However, Sell et al. found that the large hyperforin molecule might act as a protonophore independently of TRPC6, thereby altering local membrane electrical currents and affecting neurotransmitter uptake. In any case, the mechanism of action of Hypericum perforatum is clearly unusual, and its full elucidation may point the way to development of unique antidepressants.
Transient receptor potential canonical 6 knockdown ameliorated diabetic kidney disease by inhibiting nuclear factor of activated T cells 2 expression in glomerular mesangial cells
Published in Renal Failure, 2022
Jian Yu, Chunchun Li, Lisha Ma, Bin Zhai, Aiping Xu, Decui Shao
In our study, we focused on GMCs. GMCs in the interstitial cells in the kidney glomerulus are involved in the processes of DKD. In the priming of DKD, GMC activation leads to cell proliferation, overproduction of ECM proteins and thickening of the glomerular basement membrane [36,37]. Therefore, GMC activation is an indispensable factor in the initial pathophysiological changes of early DKD, but those changes will ultimately lead to glomerular sclerosis and kidney failure [38]. In our study, we observed that knockdown of TRPC6 by siRNA reduced ECM overproduction induced by HG. In neonatal pig GMCs, hyperforin-induced activation of the TRPC6 channel inhibited GMC proliferation and triggered apoptotic pathways [39]. We hypothesize that the intracellular signal transduction mediated by the TRPC6 channel might vary depending on the cell types or different pathological stimuli.
Combination of leflunomide and benazepril reduces renal injury of diabetic nephropathy rats and inhibits high-glucose induced cell apoptosis through regulation of NF-κB, TGF-β and TRPC6
Published in Renal Failure, 2019
Huili Li, Yuanyuan Wang, Zhangqing Zhou, Fang Tian, Huanhuan Yang, Juzhen Yan
The transient receptor potential cation channel 6 (TRPC6) is a kind of subfamily of nonselective cation channels permeable to Ca2+ [33]. In recent studies, it was found TRCP6 played an important role in inflammation and it mainly promoted inflammation process in diseases such as lung vascular permeability and cardiac fibrosis [34,35]. Besides, TRPC6 is also thought to be regulated by NF-κB in neuron damage [36], and has recently been proven to play important roles in development of DN. Li et al. found the activation of TRPC6 in podocytes was involved in high-glucose induced cell injury [37]. Increased TRPC6 expression is also considered to be associated with tubular epithelial cell proliferation and inflammation in DN [38]. In the present study, we demonstrated for the first time that the combination use of leflunomide and benazepril could reduce the levels of NF-κb, TGF-β and TRPC6 in both DN rats and high-glucose induced RMCs. However deeper insights are still need to give a better understanding.
ATRA attenuate proteinuria via downregulation of TRPC6 in glomerulosclerosis rats induced by adriamycin
Published in Renal Failure, 2018
Lei Zhang, Xiu-Ping Chen, He Qin, Ling Jiang, Yuan-Han Qin
However, it is currently not known how TRPC6 influences glomerulosclerosis, a growing body of evidence points out that harmful intracellular effects caused by increased cation flux cannot be ignored. This belief is not only as a mechanism of renal disease but also prevalent in models of other disease, such as cardiac disease [29]. We assume that activated TRPC6 feels the damage signal in adriamycin-induced glomerulosclerosis, and then activates downstream factors, causing the disappearance of the foot process, then changes in the glomerular filtration barrier, ultimately led to the occurrence of proteinuria. Therefore, pharmacologic TRPC6 blockade is a reasonable therapeutic option. Future research will focus on the mechanisms by which TRPC6 specific affects the pathophysiology of the renal disease.