Adenosine is a ubiquitous purine signaling molecule generated from ATP/AMP breakdown (extracellular via CD39 → CD73; intracellular via SAH → SAM cycle). Acts on four G-protein-coupled receptors with distinct G-coupling and tissue distribution. A1 (Gi/o-coupled, high abundance in brain, heart, kidney): ↓cAMP → ↓neurotransmitter release (sleep-promoting; "ado pressure" Borbély S process), bradycardia (cardiac AV node — therapeutic adenosine bolus for SVT), antinociception, ↓renal renin. A2A (Gs-coupled, striatum, blood vessels, lymphocytes, platelets): ↑cAMP → vasodilation (coronary — basis of dipyridamole/regadenoson stress testing), inhibits T-cell activation (immunosuppression — tumor microenvironment), antiplatelet (ticagrelor partial mechanism); striatal A2A on D2 MSNs antagonizes D2 → Parkinson target (istradefylline). A2B (Gs, lower-affinity, widely expressed): mast-cell activation, asthma + inflammation. A3 (Gi, cardioprotective, anti-tumor, anti-inflammation; pre-clinical agonists). Adenosine pharmacokinetics: ultra-short half-life (~10 s in plasma) — rapidly degraded by adenosine deaminase + cellular uptake via ENT1/2 (dipyridamole blocks uptake → ↑extracellular adenosine → potentiates stress test). Methylxanthines (caffeine, theophylline, theobromine, pentoxifylline) are non-selective adenosine receptor antagonists — explains stimulant, bronchodilator, ↑HR, ↑BP effects. Therapeutics: A1 — direct adenosine IV for SVT termination (transient AV block); A2A — regadenoson (CV-stress imaging — selective A2A, doesn't hit A1 bronchoconstriction); dipyridamole (uptake inhibitor → A2A-mediated coronary vasodilation, stress imaging + antiplatelet in CADASIL); ticagrelor partial A2A; istradefylline for Parkinson; A2B + A3 agonists/antagonists in clinical trials (cancer immunotherapy, fibrosis). Cross-links: caffeine demethylation (xanthines), circadian clock bmal1 per cry (sleep), platelet aggregation (antiplatelet).
Organ Systems
nervous
cardiovascular
immune-hematologic
respiratory
Pathway Steps
ATP / ADP (released — stress, ischemia, inflammation) → AMP (CD39, ENTPD1) — via ectonucleotidase; rate-limiting step in extracellular adenosine generation. Extracellular adenosine is generated on demand from released nucleotides: under stress, ischemia, or inflammation, ATP/ADP are dephosphorylated to AMP by the ectoenzyme CD39 (ENTPD1). This flips ATP’s pro-inflammatory “danger” message toward the anti-inflammatory signal that adenosine carries.
AMP → adenosine (CD73, NT5E) — via CD73 is the rate-limiting enzyme — therapeutic target in cancer immunotherapy. The rate-limiting step is CD73 (NT5E), the ecto-5′-nucleotidase that dephosphorylates AMP to adenosine. The CD39→CD73 tandem is a major immune checkpoint — tumors exploit it to generate immunosuppressive adenosine, which is why CD73 and A2A inhibitors are in cancer-immunotherapy trials.
adenosine + A1 (Gi) → ↓cAMP → ↓neurotransmitter release + bradycardia — via brain sleep-pressure; cardiac AV node block (clinical bolus for SVT). The A1 receptor couples to Gi, lowering cAMP. In heart it slows the SA/AV node (the basis of adenosine’s use to terminate SVT), and in brain it suppresses presynaptic neurotransmitter release — the inhibitory, sedative/anticonvulsant tone that caffeine blocks.
adenosine + A2A (Gs) → ↑cAMP → vasodilation + T-cell suppression — via coronary stress test; tumor microenvironment immune evasion. The A2A receptor couples to Gs, raising cAMP. It mediates coronary/peripheral vasodilation and potently suppresses T-cell activation — the dominant immunosuppressive adenosine receptor, hence A2A antagonists as cancer immunotherapeutics and the rationale for istradefylline in Parkinson’s.
adenosine + A2B (Gs) → mast-cell + inflammatory signaling — via asthma + inflammation; lower-affinity than A2A. The A2B receptor (also Gs, but low-affinity) engages mainly at the high adenosine levels of injured or hypoxic tissue, driving mast-cell and inflammatory signaling. Its low affinity makes it a sensor of pathological — not basal — adenosine, implicated in asthma and inflammatory disease.
adenosine → inosine (ADA) or recycled (ENT1/2 → SAH cycle) — via half-life ~10 s; dipyridamole blocks ENT1 uptake. Adenosine is cleared by deamination to inosine via adenosine deaminase (ADA), or recycled through ENT1/2 transporters into the intracellular SAH/methionine cycle. ADA deficiency causes a form of SCID — underscoring how toxic adenosine accumulation is to lymphocytes.
caffeine / theophylline → A1 + A2A non-selective antagonism — via reverses adenosine-mediated sleep pressure → wakefulness; bronchodilation. Caffeine and theophylline are non-selective antagonists at A1 and A2A receptors — they block adenosine’s inhibitory tone rather than stimulate directly. This is why their effects (alertness, diuresis, bronchodilation, tachycardia) mirror the opposite of adenosine’s, and why tolerance involves receptor upregulation.