Pharmacology of Adenosine Receptors and Their Signaling Role in Immunity and Inflammation

Abstract

Carbohydrates, lipids and proteins, also called "metabolic fuels" are constantly being oxidized to provide energy. Glucose is generally the primary energy source for cellular metabolism. It is catabolized by the following three main processes: glycolysis, the tricarboxylic acid (TCA or Krebs) cycle and oxidative phosphorylation, which lead to the production of ATP, the final energy-rich product that is used in many different active processes in an organism. Macromolecule synthesis, muscle contraction, active transport of ions and thermogenesis are some of the key processes that require energy. Since the mid-1920s, when ATP was discovered as a substrate used in muscle contraction, knowledge about this high-energy molecule has Pharmacology and Therapeutics 86

Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy

“…The major enzymes involved in this process are the monocarboxylate transporter MCT1 and MCT4, which are both upregulated hypoxia, though MCT4 is considered the most hypoxia-induced lactate transporter (277,351,542). Furthermore, for their tissue distribution, affinity for adenosine, the type of G protein they are coupled with, and the downstream pathway (61,62,122,155). A2A and A2B receptors are mainly involved in the control of immunity and inflammation; they are coupled to G s proteins and trigger cAMP formation (61,122,155).…”

“…Furthermore, for their tissue distribution, affinity for adenosine, the type of G protein they are coupled with, and the downstream pathway (61,62,122,155). A2A and A2B receptors are mainly involved in the control of immunity and inflammation; they are coupled to G s proteins and trigger cAMP formation (61,122,155). In contrast, A1 and A3 receptors are coupled to G i/o proteins and their activation reduces the intracellular levels of cAMP; they can elicit pro-inflammatory responses depending on the context (61,62,122,155).…”

Purinergic Signalling: Therapeutic Developments

“…P2Y 12 R activation modulates sepsis-induced inflammation ( Liverani et al, 2016 ). Adenosine, acting mainly via A 2A R, is also involved in neoplastic and inflammatory and immune-mediated disease states ( Antonioli et al, 2014a ; da Rocha Lapa et al, 2014 ; Cekic and Linden, 2016 ; Ingwersen et al, 2016 ; Zhang X. et al, 2016 ; Faas et al, 2017 ).…”

Adenosine in the Thymus

“…Intracellularly, it can be produced by three main pathways: (a) decomposition of adenine nucleotides (ATP, ADP, AMP) by ATPases, ATPase and cellular 5′ nucleotidase (c5′-NT); (b) hydrolysis of S -Adenosyl- L -homocysteine by its hydrolase; (c) phosphodiesterase-mediated degradation of cAMP ( Park and Gupta, 2012 ). Intracellularly ADO can be converted to inosine by ADA and later on to uric acid ( da Rocha Lapa et al, 2014 ). It also can be shifted back to the nucleotide pool in the form of AMP by ADO kinase ( Ramakers et al, 2011 ).…”

“…The rate limiting step in extracellular ADO formation is catalyzed by either ecto-nucleoside triphosphate diphosphohydrolases, such as CD39 that phosphohydrolyses ATP, and less efficiently ADP, in a Ca 2+ - and Mg 2+ -dependent fashion, to yield AMP ( Heine et al, 2001 ), or by members of the ecto-nucleotide pyrophosphatase/phosphodiesterase family, such as NPP1 and 3, which are also located on the cell surface, but produce AMP directly ( Stefan et al, 2006 ). AMP in turn, is rapidly degraded to ADO by soluble or membrane-bound ecto-5′-nucleotidases, such as CD73 ( da Rocha Lapa et al, 2014 ). The effect of extracellular ADO is terminated by the decomposition of ADO by ecto-ADA or by the uptake into the surrounding cells through equilibrative nucleoside transporters ( Liu and Xia, 2015 ).…”