The role of adenosine and its nucleotides in central synaptic transmission.

Less than two decades ago Sutherland and Rall (1958; Rall et al., 1957) discovered a heat stable factor now known as adenosine 3′,5′-monophosphate, which accumulated in particulate fractions of liver homogenates exposed to epinephrine. This factor activated the breakdown of glycogen by soluble cytoplasmic enzymes. Although epinephrine activates glycogenolysis in intact hepatocytes, the hormone has no such effect on the soluble enzymes. Sutherland and Rall (1960; Rall and Sutherland, 1958, 1961, 1962) proposed that epinephrine might trigger the glycogenolytic response of hepatocytes by activating the synthesis of this nucleotide (cyclic AMP) whose structure (Fig. 1) by then had been shown to contain a unique cyclic phosphate bond (Lipkin et al., 1959). The polypeptide hormone glucagon also triggers the glycogenolytic response of liver, and activates the synthesis of cyclic AMP. From these and related observations on the actions of other hormones, the concept arose that cyclic AMP functioned as an intracellular “second messenger”, synthesized in response to certain hormones and which, by activating the appropriate sequence of enzymes, produced the specific biologic response of the target cell to the hormone (Sutherland et al., 1965).

The role of cyclic nucleotides in central synaptic function.

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

Cyclic Nucleotide Phosphodiesterases: Properties, Activators, Inhibitors, Structure–Activity Relationships, and Possible Role in Drug Development

The concentration of guanosine 3',5'-cyclic monophosphate (cyclic GMP) has been examined in suspensions of freshly isolated frog rod outer segments using conditions which previously have been shown to maintain the ability of outer segments to perform a light-induced permeability change (presence of calf serum, anti-oxidant, and low calcium concentration). Illumination causes a rapid decrease in cyclic GMP levels which has a half-time approximately 125 ms. With light exposures that bleach less than 100 rhodopsin molecules in each rod outer segment, at least 10(4)-10(5) molecules of cyclic GMP are hydrolyzed for each rhodopsin molecule bleached. Half of the total cyclic GMP in each outer segment, approximately 2 X 10(7) molecules, is contained in the light-sensitive pool. If outer segments are exposed to continuous illumination, using intensities which bleach between 5.0 X 10(1) and 5.0 X 10(4) rhodopsin molecules/outer segment per second, cyclic GMP levels fall to a value characteristic for the intensity used. This suggests that a balance between synthesis and degradation of cyclic GMP is established. This constant level appears to be regulated by the rate of bleaching rhodopsin molecules (by the intensity of illumination), not the absolute number of rhodopsin molecules bleached...

https://rupress.org/jgp/article-pdf/73/5/629/1247264/629.pdf

Amplitude, kinetics, and reversibility of a light-induced decrease in guanosine 3',5'-cyclic monophosphate in frog photoreceptor membranes.

Effects of therapeutic agents on cyclic AMP metabolism in vitro.

Radioimmunoassay of cyclic AMP without precipitating antibody.

Small structural changes in a series of 7-oxabicyclo[2.2.1]heptyl acids have produced four types of agents that modify the actions of TXA2 and PG. We showed that SQ 26,655 is a TXA2 receptor agonist, SQ 28,668 and SQ 29,548 are TXA2 receptor antagonists, SQ 28,852 is a CO inhibitor, and SQ 27,986 is a PGI2/PGD2 agonist. SQ 30,077 bound reversibly with high affinity to one site in human platelet membranes. The specific binding of SQ 30,077 is competitively inhibited by the identified TXA2 receptor agonists and antagonists with an order of affinity that correlates well with their functional potencies. SQ 27,986, PDG2 and SQ 28,852 show marginal affinity, indicating that their biological actions are not mediated via the TXA2 receptor.

I.M. Michel

Papers

Effects of therapeutic agents on cyclic AMP metabolism in vitro.

Radioimmunoassay of cyclic AMP without precipitating antibody.

7-Oxabicycloheptane analogs: modulators of the arachidonate cascade.