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Pseudohypoparathyroidism
Published in Pallavi Iyer, Herbert Chen, Thyroid and Parathyroid Disorders in Children, 2020
Ambika P. Ashraf, Todd D. Nebesio
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).
Long-Term Exercise and Immune Functions
Published in Ronald R. Watson, Marianne Eisinger, Exercise and Disease, 2020
It appears that the catecholamines (epinephrine and norepinephrine) can enhance and suppress immunological reactivity depending on concentration.28 They have been shown to increase adenyl cyclase activity, thus increasing intracellular cAMP.185 This has been found to decrease both T- and B-cell responses to mitogens.59,60,186 If epinephrine was injected into subjects prior to blood being collected, the mitogen responses to phytohemagglutinin (PHA), concanavalin A (CON A) and poke weed mitogen (PWM) were significantly suppressed in vitro.61 However, when added at physiological concentrations directly to leukocyte cultures, T-cell responses were not inhibited;58 on the other hand, Ig synthesis can be enhanced in vitro.187
The Involvement of Adenylyl Cyclase And Cyclic Amp-Dependent Protein Kinases in Luteinizing Hormone Actions
Published in Mario Ascoli, Luteinizing Hormone Action and Receptors, 2019
Mary Hunzicker-Dunn, Lutz Birnbaumer
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.
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].
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.
Gene therapy to terminate tachyarrhythmias
Published in Expert Review of Cardiovascular Therapy, 2022
Kohei Kawajiri, Kensuke Ihara, Tetsuo Sasano
Adenovirus vectors have 36 kb of double-stranded DNA in the viral genome [25]. Because of its high package capacity and high transduction rate, it has been used in a preclinical model [26] and in clinical trials [27] of the cardiac region. However, adenovirus vectors can induce an intense immune and inflammatory response and have a short duration of gene expression [28]. In the Adenylyl cyclase 6 (AC6) gene transfer trial, the only clinical trial using adenovirus vectors in heart failure, there were no adverse events of strong immune response [29], but the possibility of immune and inflammatory responses may continue to be an obstacle for clinical trials in the future. In addition, the short gene expression period is an important limitation because long-term suppression is needed for the treatment of inherited arrhythmias.