Adenosine Receptors: What We Know and What We are Learning

Abstract

Adenosine, beside its role in the intermediate metabolism, mediates its physiological functions by interacting with four receptor subtypes named A(1), A(2A), A(2B) and A(3). All these receptors belong to the superfamily of G protein-coupled receptors that represent the most widely targeted pharmacological protein class. Since adenosine receptors are widespread throughout the body, they are involved in a variety of physiological processes and pathology including neurological, cardiovascular, inflammatory diseases and cancer. At now, it is ascertained that the biological responses evoked by the activation of a single receptor are the result of complex and integrated signalling pathways targeted by different receptor proteins, interacting each other. These pathways may in turn control receptor responsiveness over time through fine regulatory mechanisms including desensitization-internalization processes. The knowledge of adenosine receptor structure as well as the molecular mechanisms underlying the regulation of receptor functioning and of receptor-receptor interactions during physio and pathological conditions represent a pivotal starting point to the development of new drugs with high efficacy and selectivity for each adenosine receptor subtype. The goal of this review is to summarize what we now and what we are learning about adenosine receptor structure, signalling and regulatory mechanisms. In addition, to dissect the potential therapeutic application of adenosine receptor ligands, the pathophysiological role of the receptor subtypes in different tissues are discussed.

Extracellular guanosine regulates extracellular adenosine levels

“…These broad-ranging actions of adenosine are mediated by A 1 , A 2A , A 2B , and A 3 adenosine receptors (24,45,86), and all four adenosine receptor subtypes are members of the 7-transmembrane spanning superfamily of G protein-coupled receptors.…”

Adenosine derived from Staphylococcus aureus-engulfed macrophages functions as a potent stimulant for the induction of inflammatory cytokines in mast cells

“…It plays important roles in cardiovascular, neurological, and renal diseases (5). In addition, adenosine functions as a potent pro-inflammatory mediator and contributes to the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (6).…”

Insights into the human A1 adenosine receptor from molecular dynamics simulation: structural study in the presence of lipid membrane

“…Intermediate levels are also found in other brain regions, skeletal muscle, liver, kidney, adipose tissue, salivary glands, esophagus, colon, antrum and testis. Lung and pancreas present low levels of the A 1 ARs (Trincavelli et al, 2010).…”

“…Both the third intracellular loop and the C-terminal tail of A 1 AR are involved in G ia coupling. It has been reported that under certain conditions, the A 1 AR couples via G s to adenylyl cyclase stimulation or to G q/11 to stimulate inositol phosphate production (Trincavelli et al, 2010).…”