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Platelet-Activating Factor Receptors in the Airways
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
Detailed information about the signal transduction processes has been given in Chapter 1 in this volume, by Meurs and Zaagsma, and in Reference 221. In general, two major mechanisms have been proposed and studied in detail to illustrate the transfer of information across the cell membrane. These mechanisms include: (1) stimulated PI turnover and (2) phospholipid methylation involving the adenylate cyclase system. The PI turnover pathway employs a stimulatory G protein to activate a chain of reactions; there is an activation of Pi-specific phospholipase C and protein kinase C enzymes and the formation of IP3 and DAG. All these events may stimulate an increase in intracellular free calcium and, in turn, may act synergistically with each other. The pathway employing the second-messenger cAMP has stimulatory receptors and inhibitory receptors which both communicate with the amplifier adenylate cyclase by way of stimulatory and inhibitory transducers called G-proteins (Gs- and Gi-protein or Ns- and Ni-protein, respectively) because they require GTP to function.86 Adenylate cyclase converts ATP into cAMP.
Diseased States in Man and Other Vertebrates
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
The i.v. administration of lead acetate (10 mg per rat) leads to a 95% inhibition of the rate of pyruvate carboxylation in isolated liver mitochondria.11 A close correlation between the decrease in the inhibition of pyruvate carboxylation and a decrease in the mitochondrial ATP concentration was observed. Since there was no change in the total pyruvate carboxylase activity, it was concluded that lead inhibits flux from pyruvate to oxaloacetate by decreasing the concentration of ATP.11 Subacute or chronic ingestion of lead causes an increase in the amount of pyruvate carboxylase activity in extracts of the kidney. In the chronic state, this increase was found to be associated with an increase in the activity of adenyl cyclase.823
Receptors and Signal Transduction Pathways Involved in Autonomic Responses
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The biochemical basis for the role of cAMP as the second messenger mediating the effects of β-adrenoceptor stimulation has its origins in the well known metabolic effect of adrenaline upon hepatic glycogenolysis: the conversion of glycogen to glucose-1-phosphate. This is a β2-adrenoceptor-mediated biochemical process first described in detail by Sutherland (Sutherland & Rall 1960) (Figure 13.7). Adenylyl cyclase is coupled to the β-adrenoceptor by the Gs regulatory protein, activation of the enzyme being induced by agonist occupation. Adenylyl cyclase catalyses the convertion of adenosine triphosphate (ATP) to adenosine 3’,5’-monophosphate (cyclic AMP, cAMP) driven by the subsequent hydrolysis of the released pyrophosphate. Normally, cAMP is very stable but is destroyed by the presence of phosphodiesterases (PDE). PDEs convert cAMP to the inactive non-cyclic adenosine monophosphate and their pharmacological relevance will be considered in more detail later.
Novel therapeutic approaches in the management of chronic kidney disease: a narrative review
Published in Postgraduate Medicine, 2023
Panagiotis Theofilis, Aikaterini Vordoni, Rigas G. Kalaitzidis
The administration of guanylate cyclase (GC) activators could also be efficacious in improving the treatment targets in diabetic CKD. In humans, soluble guanylate cyclase is a receptor for nitric oxide (NO). It is an important and established target in improving cardiovascular and renal diseases. It is expressed in the arterial system of the kidneys and neuroendocrine cells, contributing to the regulation of renal perfusion and renin excretion [56]. GC is activated by NO and induces the production of cyclic guanin monophosphate (cGMP) from guanosine triphosphate [57]. The complex NO/cGMP has an important effect on renal blood flow, along with anti-inflammatory, anti-fibrotic, and anti-proliferative actions in vascularized and non-vascularized regions of the renal cortex [58]. The dysregulation of NO-GC-cGMP is associated with an increased risk of CKD. It is believed that targeting the NO-sGC-cGMP axis is a potential therapeutic target, which may confer renal protection in experimental models. sGC can also be activated pharmacologically through specialized stimulators and activators, such as BI 685,509. Several trials are underway (NCT04750577, NCT04736628), and the role of this drug class in renal protection is still to be determined.
QPCTL regulates macrophage and monocyte abundance and inflammatory signatures in the tumor microenvironment
Published in OncoImmunology, 2022
Kaspar Bresser, Meike E. W. Logtenberg, Mireille Toebes, Natalie Proost, Justin Sprengers, Bjorn Siteur, Manon Boeije, Lona J. Kroese, Ton N. Schumacher
The current study has the following limitations: 1) Germline deletion of QPCTL may potentially lead to developmental alterations that influence the host’s response to tumor challenge, for example, affecting the capacity of certain CAF or immune subsets to differentiate, independent of QPCTL activity during tumor outgrowth. However, the absence of clear phenotypic alterations at baseline, and the fact that an increased Mφ-Mo-ratio was observed in wild-type mice challenged with QPCTL-deficient tumor cells, argue against this possibility. 2) In the present study, we have aimed to model the effects of depletion of QPCTL activity on the tumor micro-environment, whereas glutaminyl cyclase inhibitors will, based on the similarity of their active sites, likely inhibit both QPCTL and QPCT activity.38,39 Such inhibition of QPCT may be relevant as siRNA-mediated suppression of QPCT has been shown to reduce expression of CCL2, CX3CL1 and CD54/ICAM.12 In future work, dual inactivation of QPCTL and QPCT may form a means to test this.
Targeting circadian PER2 as therapy in myocardial ischemia and reperfusion injury
Published in Chronobiology International, 2021
Yoshimasa Oyama, Lori A Walker, Tobias Eckle
Not surprisingly, studies exploring liver metabolism under light-dark cycles and constant darkness identified adenosine as a circulating circadian signaling molecule (Zhang et al. 2006). These studies implicated adenosine signaling as a mechanism for synchronizing the central and the peripheral clock. Indeed, our group found that intense light increased cardiac adenosine levels under normoxia (Figure 1). Further, Adora2b deficiency in mice resulted in abolished light-cardioprotection. Therefore, we have proposed that adenosine signals the ‘cardioprotective’ effect of light from the brain to the heart. However, our studies were restricted to the use of whole-body knockout mice. Future studies in mice with a brain-specific deletion of adenosine signaling will be necessary to fully understand the role of adenosine in peripheral clock synchronization. Regardless, one drug class that can reset the circadian system and induce the circadian protein PER2 are cAMP enhancers (Ripperger and Albrecht 2012), as cAMP is the core component of PER2 regulation (Wang and Zhou 2010). Forskolin, an adenylyl cyclase activator, is the prototype of such a drug (Wang and Zhou 2010). Besides, our laboratory studies found that the ADORA2B receptor is a potent inducer of cardiac PER2 by enhancing cAMP signaling pathways (Eckle et al. 2012). Moreover, Per2 deficiency completely abolished the specific ADORAB2 agonist BAY 60–6583 mediated protection from myocardial ischemia (Eckle et al. 2012). Together, these studies highlight the use of ADORA2B agonists to activate circadian mediated cardioprotection (Figure 2).