It is well known that ATP is released from many cells where cell membranes subjected to stretch, perhaps via one of the above mentioned mechanisms. ![]() in necrotic cell death, 2) release from large storage vesicles containing hormones, 3) via connexin/pannexin “hemichannels”, 4) from transport vesicles delivering proteins to the cell membrane, and 5) from a subset of lysosomes. Several additional mechanisms have now moved to the foreground: 1) release from cells with damage to the cell membrane e.g. when work load is markedly enhanced or when the supply of oxygen and glucose is limiting as in ischemia.ĪTP might, as originally proposed, act as a neurotransmitter, stored and released together with other transmitters, sometimes ATP may be preferentially released via so called ”kiss-and-run” mechanism. Adenosine is formed intracellularly whenever there is a discrepancy between the rates of ATP synthesis and ATP utilization e.g. From this baseline level adenosine can increase substantially via several mechanisms: 1) formation intracellularly and export via transporters, and 2) formation in the extracellular space from adenine nucleotides released from cells. ![]() Since most if not all cells possess equilibrative adenosine transporters, there will, by necessity, be also a finite level of adenosine in the extracellular space, even under the most basal conditions. Regulation of adenosine levels – increasing in stressful situationsīecause it is a key metabolite there is always a finite intracellular concentration of adenosine. Furthermore, there is no really good reason to divide the receptors into high affinity and low affinity receptors as is sometimes done. Thus, the potency of endogenous adenosine depends both on receptor number, and on the type of response measured. If, by contrast, we instead examine the ability to activate MAP kinase (which all the receptors do), adenosine is equipotent at all of them. When this is done it is observed that adenosine is equipotent at A 1, A 2A and A 3 receptors, but is some 50 times less potent at A 2B receptors if alterations in cAMP are recorded. It is therefore important to compare potencies between receptors at comparative receptor densities. In such systems alterations in receptor number is manifested by parallel shifts in the dose response curve, not as alterations in the maximal response. Adenosine receptors generally exhibit the behaviour described by pharmacologists as ”spare receptors”. This introduces another important confounding factor: potency of the agonist is markedly influenced by the receptor number. The potency of adenosine must therefore be measured in functional assays. Therefore, if metabolism of the labelled added adenosine is prevented, endogenous adenosine accumulates to confound the measurements, and we do not have reliable data on the comparative affinity of the endogenous agonist at the four adenosine receptors. ![]() The reason is that adenosine is rapidly metabolized and also rapidly formed in biological preparations including membrane preparations. Unfortunately it proves very difficult to determine the affinity of adenosine to the receptors by direct binding studies. Potency of adenosine - Dependence on receptor number and on response measured These pathophysiological roles of adenosine also offer some potential drug targets, but the fact that adenosine receptors are involved in so many processes does not simplify drug development. Adenosine levels rise in stress and distress (up to 30 μM in ischemia) and tend to minimize the risk for adverse outcomes by increasing energy supply and decreasing cellular work, by stimulating angiogenesis, mediating preconditioning and having multiple effects on immune competent cells. Here adenosine can play a physiological role and here antagonists such as caffeine can have effects in healthy individuals. The endogenous agonist, adenosine, has a minimal concentration in body fluids (20 – 200 nM) that is sufficient to slightly activate the receptors where they are very highly expressed - as in the basal ganglia, on fat cells and in the kidney. They are well conserved and widely expressed. There are four adenosine receptors, A 1, A 2A, A 2B and A 3, together forming a defined subgroup of G protein coupled receptors.
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