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Insulin Signaling Modulates Neuronal Metabolism
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Qian Huang, Jialin Fu, Kelly Anne Borges, Weikang Cai
The ER is the largest reservoir and central to the intracellular Ca2+ homeostasis that maintains the normal metabolism and function of neurons (148–150). With the expression of high density of Ca2+ channels and transporters, the ER in neurons can rapidly uptake or release Ca2+ in response to various intracellular signaling pathways. One of the major signaling pathways controlling Ca2+ release from ER is G-protein-coupled receptor (GPCR)/Gq/phospholipase Cβ (PLC beta) cascade. Thus, activation of Gq-PLCβ cascade results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), and the production of diacyl glycerol (DAG) and inositol-1,4,5-triphosphate (IP3). IP3 opens IP3 receptor (IP3R) and ryanodine receptor (RyR) on the ER, releasing Ca2+ stored in the lumen of the ER into the cytoplasm. Subsequently, the cytosolic Ca2+ concentration (i.e. [Ca2+]i) spike elicits an array of downstream signaling events for synaptic remodeling, axon guidance, dendritic spine growth, synaptic vesicle release, and gene expression (144–146).
Cognition Enhancers
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Ramneek Kaur, Rashi Rajput, Sachin Kumar, Harleen Kaur, R. Rachana, Manisha Singh
In protein kinase B (PKB) signaling pathway, TrkB acts over sequences of phosphorylation steps involving Akt, mammalian target of rapamycin (which controls translation of mRNA), and PI3K. It involves phospholipase Cγ whose function is to cleave the phospholipids at phosphate site, thus, forming 1, 2-diacylglycerol and inositol 1, 4, 5-triphosphate (IP3). IP3 is an essential secondary messenger for the IP3 receptor on endoplasmic reticulum (ER) that is a main constituent of ryanodine receptor (RyR) and calcium-induced calcium release (Song et al., 2005).
Physiological Properties of the Lower Urinary Tract
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
M3 receptors are coupled to Gq/11 proteins, which importantly activate the enzyme phospholipase C (PLC) to convert membrane phosphoinositides to the second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 in turn releases Ca2+ from intracellular stores, after binding to an IP3 receptor, to activate the contractile proteins. There is a body of experimental evidence to support the relevance of this pathway in detrusor: muscarinic agonists generate a rise in [Ca2+] independent of membrane potential, and its release is blocked by IP3 receptor blockers (70); the potency of the muscarinic receptor agonist carbachol is reduced by other IP3 receptor blockers such as heparin and PLC inhibitors (84). Moreover inositol phosphate production mirrors tension generation in detrusor strips exposed to muscarinic agonists (85). However, other work suggests that this is not the exclusive pathway, in part because of the relative ineffectiveness of other PLC inhibitors to reduce carbachol-induced tension. It has been suggested that activation of the rho-kinase pathway and of protein kinase C by G protein activation and DAG, respectively, reduces the activity of myosin light chain phosphatase to increase the Ca2+ sensitivity of the contractile proteins; the rise of intracellular Ca2+ is explained by activation of nonspecific cation channels coupled to L-type Ca2+ channel activation (86). Several attempts to reconcile this controversy have been attempted, and it may be that there are considerable species differences in the relative importance of inositol phosphate and other pathways (87).
Myosin light chain kinase regulates intestinal permeability of mucosal homeostasis in Crohn’s disease
Published in Expert Review of Clinical Immunology, 2020
Agonists activate G-coupled receptors and phospholipase C (PLC), further leading to PIP2 hydrolysis and producing the second messengers diacylglycerol (DAG) and Inositol triphosphate (IP3) [96]. DAG/IP3 (Figure 3(b)) related to MLCK regulation (PLC-β -IP3/DAG-MLCK signaling) is often accompanied by calcium [97]. IP3 binds specific receptors on the endoplasmic reticulum (ER) before IP3-dependent Ca2+ release from IP3 receptor channels. DAG and Ca2+ activate PKC, which, together with the Ca2+-CaM-dependent pathway activates MLCK [98–100]. IP3 binds specific receptors on the ER to mobilize Ca2+ from the internal stores. DAG and Ca2+ activate PKC, which stimulates cell growth.
Mechanisms of octanoic acid potentiation of insulin secretion in isolated islets
Published in Islets, 2019
Tingting Zhang, Pan Chen, Charles A. Stanley, Toshinori Hoshi, Changhong Li
The potentiating effect of OA on insulin secretion has been recognized since the 1960s; however, the potentiating mechanism has remained unclear. Our results here indicate that OA itself is a very weak insulin secretagogue but has a strong potentiating effect on fuel-stimulated insulin secretion. The potentiating effect of OA is unlikely to be mediated by β-oxidation of octanoate, but is Ca2+ dependent and appears to involve VSACs. Furthermore as a down-stream pathway after plasma membrane events, IP3 receptors on in endoplasmic reticulum, a key component in intracellular Ca2+ homeostasis, indirectly regulates the OA potentiation effect.
Roles of CRAC channel in cancer: implications for therapeutic development
Published in Expert Review of Precision Medicine and Drug Development, 2020
Husain Yar Khan, Iqra Mazahir, Shriya Reddy, Farzeen Fazili, Asfar Sohail Azmi
Ca2+ signaling in the cells gets activated either by the release of Ca2+ stored in the endoplasmic reticulum or the influx of extracellular Ca2+ into the cells. CRAC channel functions to combine and coordinate these two routes through which intracellular Ca2+ signaling may be induced. Figure 1 shows the mechanism of their activation under physiological conditions. The first step in the activation of CRAC channel involves the stimulation of cell surface receptors, such as G-protein coupled receptors (GPCRs) or receptors tyrosine kinases (RTKs), through binding of their respective ligands (agonists), that activates membrane-bound enzyme phospholipase C (PLC), which in turn hydrolyzes membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). The subsequent binding of IP3 to the Ca2+ permeable IP3 receptors located on the endoplasmic reticulum membrane elicits the release of Ca2+ from the endoplasmic reticulum into the cytosol [23,34]. This results in the depletion of Ca2+ levels in the lumen of endoplasmic reticulum, which is eventually sensed by STIM proteins. Consequently, STIM proteins respond by oligomerizing and translocating to the junction of endoplasmic reticulum and plasma membrane where they form large clusters, termed as STIM puncta. A cytoplasmic CRAC activation domain (CAD) on the C terminus of STIM directly interacts with the intracellular C terminus of Orai [35,36]. This physical coupling of STIM and Orai proteins induces the opening of CRAC channel, thereby allowing the influx of extracellular Ca2+ into the cytosol. Ultimately, such an influx of Ca2+ facilitates the replenishment of the depleted intracellular Ca2+ stores, in addition to evoking the activation of the Ca2+ associated signal transduction pathways.