Summary
Adenosine may well be as important in the regulation of adenylate cyclase as hormones. Sattin and Rall first demonstrated in 1970 that adenosine was a potent stimulator of adenylate cyclase in the brain. However, adenosine is an equally potent inhibitor of adenylate cyclase in other cells such as adipocytes. The concentration of adenosine required for this regulation of adenylate cyclase is in the nanomolar range (10 to 100 nm). Both the inhibitory and stimulatory effects of low concentrations of adenosine on adenylate cyclase are antagonized by methylxanthines. This antagonism of adenosine action may account for all or part of the effects of methyl xanthines on cyclic AMP levels in many tissues. Adenosine appears to be a particularly important endogenous regulator of adenylate cyclase in brain, smooth muscle and fat cells. Under conditions in which intracellular AMP rises, adenosine formation and release is accelerated. In addition to its direct effects on adenylate cyclase, adenosine (at higher concentrations approaching millimolar) exerts multiple effects on cellular metabolism as a result of its intracellular metabolism and especially conversion to nucleotides.
The effects of nanomolar concentrations of adenosine on adenylate cyclase are mediated through an adenosine site possessing strict structural specificity for the ribose moiety of the molecule (the “R” adenosine site) which is presumably located on the external surface of the plasma membrane. In brain, lung, platelets, bone, lymphocytes, skin, adrenals, Leydig tumors, and coronary arteries adenosine stimulates adenylate cyclase via this site. However, in rat adipocytes, brain astroblasts and ventricular myocardium adenosine inhibits adenylate cyclase through the “R” or adenosine site. Although the “R” site requires an intact ribose moiety, adenosine analogs modified in the purine ring such as N6-phenylisopropyladenosine appear to be potent agonists for this site. All effects of adenosine mediated via the “R” site are competitively antagonized by methyl xanthines.
The effects of micromolar concentrations of adenosine appear to be mediated via a site with strict structural specificity with respect to the purine moiety of the molecule (the “P” or adenine adenosine site). This “P” site is postulated to be located on the intracellular face of the plasma membrane and mediates the effects of adenosine due to conversion of adenosine to 5′-AMP or perhaps other nucleotides. The effects of high concentrations of adenosine are always inhibitory to adenylate cyclase activity, are readily demonstrated in broken cell preparations, and are unaffected by methylxanthines. An intact purine ring is required for these adenosine effects but modifications of the ribose moiety of the molecule generally increases the potency of the analog. A prime example is 2′,5′-dideoxyadenosine, which is the most potent known “R”-site specific adenosine analog.
We propose a unitary model which explains both the stimulatory and inhibitory effects of low concentrations of adenosine on adenylate cyclase. In brief, adenylate cyclase is postulated to exist in three interconvertible activity states: (i) an inactive state (E0); (ii) a GTP-liganded state with high activity (EGTP); and (iii) a GDP-liganded state (EGDP) which is inactive in cells where adenosine stimulates adenylate cyclase, but active in cells where adenosine inhibits adenylate cyclase. We postulate that the enzyme cycles through these states in the following manner: the E0 state binds GTP and forms the EGTP state; hydrolysis of bound GTP converts the EGTP to the EGDP state; and release of bound GDP converts EGDP to the E0 state. The E0 state is the only form of the enzyme which can be stimulated by either hormones or GTP and its formation from the EGDP state is rate-limiting in this cycle. The conversion of EGDP to E0 regulates the ability of hormones and GTP to activate adenylate cyclase and is postulated to be adenosine sensitive.
In cells where both EGDP and E0 states are inactive, adenosine stimulates adenylate cyclase activity. In cells where E0 is inactive, but EGDP is active, adenosine inhibits adenylate cyclase activity. In addition we suggest that in cells where adenosine inhibits adenylate cyclase activity (cells postulated to have an EGDP state which is active) high concentrations of GTP favor accumulation of the enzyme in EGDP and thus are inhibitory to activity. Prostaglandins may also regulate adenylate cyclase in a manner similar to that described above for adenosine.
We conclude that adenosine is an important regulator of adenylate cyclase whose role has only been appreciated recently. Further studies are warranted on both its binding to cells and mechanisms by which it regulates adenylate cyclase.
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This work was supported by United States Public Health Service Research Grant AM-10149 from the National Institute of Arthritis, Metabolism and Digestive Diseases.
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Fain, J.N., Malbon, C.C. Regulation of adenylate cyclase by adenosine. Mol Cell Biochem 25, 143–169 (1979). https://doi.org/10.1007/BF00235364
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DOI: https://doi.org/10.1007/BF00235364