Receptors and Signal Transduction Pathways Involved in Autonomic Responses
Kenneth J. Broadley in 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.
The Involvement of Adenylyl Cyclase And Cyclic Amp-Dependent Protein Kinases in Luteinizing Hormone Actions
Mario Ascoli in Luteinizing Hormone Action and Receptors, 2019
In this chapter we will review structural and functional aspects that regulate cyclic AMP formation by the enzyme adenylyl cyclase and how cyclic AMP generated as a consequence of hormonal stimulation of adenylyl cyclase regulates the cellular response. With respect to the first of the two main areas to be covered, we will discuss the basic structure and regulation of adenylyl cyclase by nucleotides and Mg, we will speculate on several aspects of activity regulation of the signal-transducing proteins that couple receptors to the adenylyl cyclase proper, and we shall analyze what is known about the regulation of the hormone-receptor interaction by the coupling proteins and what might be learned from it. As applied specifically to LH receptors, we will discuss possible mechanisms involved in the turn-off mechanism that is alternative to hormone dissociation from the system, i.e., desensitization processes. With respect to the second of the areas to be covered, we will review the evidence that exists that cyclic AMP, acting via protein kinase activation and subsequent protein phosphorylation, mediates in a physiologically meaning way steroidogenesis in LH target cells. Finally, we will address the question as to how intracellular specificity of the second messenger cyclic AMP is thought to be achieved.
Pseudohypoparathyroidism
Pallavi Iyer, Herbert Chen in Thyroid and Parathyroid Disorders in Children, 2020
The interaction between these hormones and their specific G protein coupled receptors activates the α-subunit of the stimulatory G protein (Gsα, encoded by GNAS) leading to dissociation of the α-subunit of the heterotrimeric stimulatory G protein from the β and γ subunits. The activation by Gsα of adenylyl cyclase leads to synthesis of the intracellular messenger cyclic AMP (cAMP). Protein kinase A (PKA) is a primary target of cAMP, and the binding of cAMP to Type 1 Regulatory Subunit 1 Alpha (PRKAR1A) results in a cascade of intracellular events, including the phosphorylation of phosphodiesterases (PDEs), such as PDE4D. Figure 12.1 illustrates the cAMP-mediated signaling pathway. The underlying molecular defect in PHP varies from lack of activation at the receptor through molecular defects affecting the Gsα or abnormalities in the downstream signaling pathways, namely PRKAR1A and PDE4D (Gsα/cAMP/PKA pathway) (1).
Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zhi Li, Lijuan Kou, Xinzhen Fu, Zeping Xie, Maolei Xu, Lin Guo, Tiantian Lin, Shizhou Gong, Shumin Zhang, Ming Liu
Adenosine is one of the most important signalling molecules in the human body, and it exerts its effects through G-protein coupled receptors, including A1, A2A, A2B, and A3 adenosine receptors (ARs)1–3. Upon activation by adenosine, A2A AR and A2B AR promote adenylyl cyclase (AC) activation and subsequent cyclic AMP (cAMP) production4,5. Elevated intracellular cAMP in T cells will result in T cell anergy by reducing its proliferation, maturation, cytokine production (e.g., IL-2), and tumour-killing activity6–8. The cell cytotoxicities of natural killer cells, dendritic cells, or macrophages are inhibited by this pathway as well9–11. In the tumour microenvironment (TME), the level of extracellular adenosine is higher than that of normal tissue, leading to immune evasion4,12,13. A2A and A2B ARs are widely considered critical to the immune functions of adenosine. The relevance of A2 receptors in tumour immunotherapy has stimulated the development of various selective antagonists for these receptors14–19.
Genetic and epigenetic studies of opioid abuse disorder – the potential for future diagnostics
Published in Expert Review of Molecular Diagnostics, 2023
Sarah Abdulmalek, Gary Hardiman
As mentioned above, opioid receptors belong to the G protein-coupled receptor (GPCR) family and are heavily distributed throughout the CNS and some peripheral organs. When activated, opioid receptors trigger signaling cascade through their main functional subunits, Gα and Gβγ. Adenylyl cyclase (AC) is one of the main effectors of the G-protein subunits in which stimulation or inhibition of certain AC isoforms serves different functions. In general, Gαs stimulates all AC isoforms from AC I – AC IX and only AC I, V, VI are inhibited by Gαi/o. On the other hand, AC II, IV, and VII are stimulated by Gβγ while AC I, V, VI, and VIII are inhibited by the same subunit. Besides AC, Gβγ subunits also regulate different effectors such as, but not limited to, G protein-gated inwardly rectifying K+ channel (GIRK), G protein-coupled receptor kinase (GRK) 2/3, phospholipase Cβ (PLCβ), phosphatidylinositol-3-kinase (PI3K) [52].
Role of GPR40 in pathogenesis and treatment of Alzheimer's disease and type 2 diabetic dementia
Published in Journal of Drug Targeting, 2019
Jing-Jing Chen, Yu-Hang Gong, Ling He
Glucagon-like peptide 1 (GLP-1) has many remarkable effects such as improving central satiety, expanding insulin sensitivity, increasing glucose-stimulated insulin secretion and reducing hepatic gluconeogenesis [8]. In enteroendocrine cells, the activation of GPR40 stimulates the release of GLP-1 and glucose-dependent insulinotropic peptide (GIP) [62,63]. GPR40 generally couples with the Gq or Gs protein until activated by the full agonist (Gq and Gs agonist) or the free fatty acid (Gq only agonist). Isolated Gq protein activated PLC, increasing IP3 levels. Subsequently, Ca2+ was released from the endoplasmic reticulum and slightly stimulating incretin secretion. In addition, the separated Gs subunit activated adenylyl cyclase, leading to an increase in cAMP. Then, cAMP-activated protein kinase A (PKA) signalling [57,62].