Beneficial and detrimental role of adenosine signaling in diseases and therapy

Abstract

Adenosine is a major signaling nucleoside that orchestrates cellular and tissue adaptation under energy depletion and ischemic/hypoxic conditions by activation of four G protein-coupled receptors (GPCR). The regulation and generation of extracellular adenosine in response to stress are critical in tissue protection. Both mouse and human studies reported that extracellular adenosine signaling plays a beneficial role during acute states. However, prolonged excess extracellular adenosine is detrimental and contributes to the development and progression of various chronic diseases. In recent years, substantial progress has been made to understand the role of adenosine signaling in different conditions and to clarify its significance during the course of disease progression in various organs. These efforts have and will identify potential therapeutic possibilities for protection of tissue injury at acute stage by upregulation of adenosine signaling or attenuation of chronic disease progression by downregulation of adenosine signaling. This review is to summarize current progress and the importance of adenosine signaling in different disease stages and its potential therapeutic effects.

Keywords: adenosine signaling; disease; hypoxia; therapy.

Fig. 1.

Metabolism of adenosine signaling. Cells release ATP through connexins or pannexins channels under hypoxia and other stress conditions. The accumulation of extracellular ATP is dephosphorylated to adenosine (A) by 2 ecto-nucleotidases including CD39 and CD73. Adenosine can further be metabolized by adenosine deaminase (ADA) to inosine or functions as a signaling molecule by activation of its adenosine receptors (AR) on multiple cell types. Once uptake by equilibrative nucleoside transporters (ENTs), adenosine is further metabolized by adenosine kinase (ADK) to AMP, adenosine deaminase (ADA) to inosine, or S-adenosylhomocytesine hydrolase (SAHH) to adenosylhomocysteine (AdoHcy).

Fig. 2.

Adenosine receptor-mediated signaling pathways. Extracellular adenosine functions as signaling molecule by engaging cell surface adenosine receptors (ADORA1, ADORA2A, ADORA2B, and ADORA3). ADORA1 and ADORA3 adenosine receptors are coupled to adenylyl cyclase (AC) by the inhibitory G-protein subunit (Gα_i) and thereby can lower intracellular levels of the second messenger cyclic adenosine monophosphate (cAMP). In contrast, the ADORA2A and ADORA2B adenosine receptors can induce AC by the stimulatory G-protein subunit (Gα_s) and therefore can induce intracellular cAMP levels. Activation of both ADORA1 and ADORA2B stimulates phosphatidylinositol 3-kinase (PI3K)/AKT pathway, and activation of both ADORA2A and ADORA2B induces release of ROS, EETs, and PGI₂. PKA, protein kinase A; PLC, phospholipase C; ROS, reactive oxygen species; EETs, epoxyeicosatrienoic acids; PGI₂, prostacyclin; eNOS, endothelial NO synthase; NO, nitric oxide; IL-6, interleukin 6; MAPK, mitogen-activated protein kinases; ERK, extracellular signal-protein kinase.