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Biomedical subjects

J Axelrod

Publications and source records attributed to J Axelrod.

At least 163 records · Page 9Linked to original sources
PubMed1976

Subcellualr distribution of protein carboxymethylase and its endogenous substrates in the adrenal medulla: possible role in excitation-secretion coupling.

Protein carboxymethylase (S-adenosyl-L-methionine:protein O-methyltransferase, EC 2.1.1.24) transfers a methyl group from S-adenoxyl-L-methionine to carboxyl side chains of proteins to form labile protein-methyl esters which, thus, neutralize negative charges. This enzyme was examined for its possible participation in excitation-secretion coupling in the adrenal medulla. Protein carboxymethylase has a specific activity several times higher in the adrenal medulla than in the adrenal cortex; also, the medulla has a higher concentration of methyl-acceptor proteins. In the adrenal medulla, 97% of the enzyme was localized in the cytosol. Of the various subcellular fractions of the medulla, the catecholamine-containing chromaffin vesicles had the highest concentrations of substrat(s) for protein carboxymethylase. Carboxymethylation of proteins in intact chromaffin vesicles results in stripping of methylated protein(s) from the membranes. Thus, protein carboxymethylase appears to be involved in the neutralization of charges on the surface of chromaffin vesicles and in the release of surface proteins; both phenomena are likely to be required for exocytosis.

Adrenal Cortex↗
PubMed1976

Localization of triiodothyronine in nerve ending fractions of rat brain.

Radioactive triiodothyronine reaching the rat brain after intravenous administration is rapidly and selectively taken up in the nerve ending fraction. A concentration gradient of radioactivity from brain cytosol to synaptosomes is observed at 5 min, increases linearly over the first hour, and is maintained for at least 10 hr. Radioactivity in the synaptosomes is due to triiodothyronine (90%) plus a single unidentified metabolite (10%). Approximately 85% of the synaptosomal radioactivity is released by osmotic disruption of the particles. The process of selective uptake, concentration, and retention of triiodothyronine in nerve terminals of the rat brain may be related to the sympathomimetic and behavior-altering effects of the thyroid hormones.

Animals↗
PubMed1976

Biosynthesis and metabolism of endogenous tyramine and its normal presence in sympathetic nerves.

By use of a sensitive and specific enzymatic isotopic method for the determination of tyramine, the small quantities of this amine which are present endogenously in rat tissues, including brain, heart, kidney and salivary gland, have been quantitated. The levels of tyramine in brain were increased to a similar extent by injecting animals with a monoamine oxidase inhibitor, pargyline, and a dopamine beta-hydroxylase inhibitor, FLA-63; in contrast, pretreatment of animals with alpha-methyl-para-tyrosine, a tyrosine hydroxylase inhibitor, did not lead to an increase in tyramine levels in brain. Pretreatment of rats with 6-hydroxydopamine resulted in a marked diminution in the tyramine content of rat atria and salivary gland. Denervation of the salivary gland decreased the endogenous level of tyramine approximately 50% in denervated glands compared to undenervated glands. These results suggest that tyramine exists at least partly in sympathetic nerves in many tissues.

Animals↗
PubMed1976

Pineal beta adrenergic receptor: correlation of binding of 3H-l-alprenolol with stimulation of adenylate cyclase.

3H-l-Alprenolol, a potent competitive beta adrenergic antagonist, binds to sites in rat pineal gland membranes. The properties of these binding sites were compared to those of the receptors which mediate the beta adrenergic activation of pineal adenylate cyclase. Both sites are highly stereospecific. The l-stereoisomers of alprenolol and propranolol were at least two orders of magnitude more potent than the d-stereoisomers in inhibiting isoproterenol-stimulated adenylate cyclase or 3H-l-alprenolol binding. The dissociation constants (Kd) of the l-stereoisomers of both alprenolol and propranolol were 10 to 22 nM as determined by competition for binding sites or by inhibition of isoproternol-stimulated adenylate cyclase. Beta adrenergic agonists which stimulated adenylate cyclase also competitively inhibited the binding of 3H-l-alprenolol. They showed the same order of potency (isoproterenol greater than norepinephrine greater than or equal to epinephrine) and the same individual affinities in the two systems. Alpha adrenergic blockers were ineffective in inhibiting either adenylate cyclase stimulation or 3H-l-alprenolol binding. Isoproternol stimulation of adenylate cyclase acrivity, and 3H-l-alprenolol binding, were rapid and rapidly reversible. The 3H-l-alprenolol binding sites were saturable and bound 0.6 pmol of ligand per mg of added protein. The data suggest that the binding of 3H-l-alprenolol occurs at sites indistinguishable from the pineal beta adrenergic receptor.

Adenylyl Cyclases↗
PubMed1976

Octopamine as a putative neurotransmitter.

Octopamine is a normally occurring amine in nervous tissues in many species of animals. In mammals, octopamine is formed from tyramine through beta-hydroxylation by DBH in the sympathetic nerves, and it is partially stored in nerve endings with a subcellular distribution similar to that of NE. It is capable of replacing NE in its storage sites, and it is released by sympathetic nerve stimulation. High concentrations are found in the crustacean central nerve cord. Specific octopamine-containing cells have been identified in Aplysia and other lower animals. On the basis of neurophysiological evidence, the existence of specific octopamine receptors in Aplysia has been postulated. In insects, octopamine produces specific biochemical responses such as increased synthesis of cyclic AMP and phosphorylase activation. The present evidence strongly suggests that octopamine may function as a neurotransmitter in lower animals. Although the physiological role of this amine has not been established in mammals, it appears likely that octopamine may function as a cotransmitter together with NE in the peripheral sympathetic nervous system.

Adenylyl Cyclases↗
PubMed1975

Regulation of sensitivity to beta-adrenergic stimulation in induction of pineal N-acetyltransferase.

Stimulation by isoproterenol causes large increases in the activity of rat pineal N-acetyltransferase (arylamine acetyltransferase or acetyl-CoA:arylamine N-acetyltransferase, EC 2.3.1.5) after a variable lag period. Lengthening periods of exposure to light cause rapid increases in the sensitivity of pineal N-acetyltransferase to induction by isoproterenol. This supersensitivity, which develops gradually over a 12 hr period, is correlated with increasingly longer lag periods in the induction of the enzyme, and with progressively greater maximal response. Repeated administration of isoproterenol to supersensitive animals rapidly reverses the above changes and causes relative subsensitivity. The sensitivity of N-acetyltransferase to induction by dibutyryl-cyclic tamp added to pineals in organ culture was found to change in parallel with the sensitivity to isoproterenol. Stimulation of cyclic AMP levels in the pineal by isoproterenol was also greater in supersensitive rats than in the subsensitive animals, whether the supersensitivity had been caused by denervation or by exposure to light for 12 hr. The above experiments suggest that there are two sites for the regulation of the sensitivity of N-acetyltransferase to induction by catecholamines. The first site regulates the capacity of intracellular processes (i.e., induction of tn-acetyltransferase) to respond to cyclic AMP as a second messenger.

Acetyltransferases↗
PubMed1975

Beta-adrenergic stimulation of pineal N-acetyltransferase: adenosine 3':5'-cyclic monophosphate stimulates both RNA and protein synthesis.

The lag period in the induction of rat pineal N-acetyltransferase (arylamine acetyltransferase or acetyl-CoA:arylamine N-acetyltransferase EC 2.3.1.5) by catecholamines via the beta-adrenergic receptor varies with the length of exposure of the rat to light or darkness. If rats have been exposed to light and reduced sympathetic nerve activity for more than 12 hr, this lag period is 1-2 hr long. Under these conditions, actinomycin D completely blocks the induction of N-acetyltransferase by isoproterenol and by dibutyryl adenosine 3':5'-cyclic monophosphate (cyclic AMP). In contrast, if enzyme activity is caused to fall by brief exposure to light at night when N-acetyltransferase activity is high, reinduction by catecholamines occurs almost immediately. In this case, actinomycin D does not block the reinduction of N-acetyltransferase by isoproterenol or by dibutyryl cyclic AMP. Cycloheximide blocks N-acetyltransferase induction under all conditions tested. Thus, new protein synthesis is always required for N-acetyltransferase induction; however, the requirement for RNA synthesis is variable, and contributes to the length of the lag period for induction. It is postulated that both beta-adrenergic stimulation and dibutyryl cyclic AMP act intracellularly at two separate sites in the induction of pineal N-acetyltransferase. One site is in the stimulation of transcription, and the other is in the stimulation of post-transcriptional events.

Acetyltransferases↗
PubMed1975

Rapid changes in rat pineal beta-adrenergic receptor: alterations in l-(3H)alprenolol binding and adenylate cyclase.

The properties of the beta-adrenergic receptor which regulates adenylate cyclase [ATP pyrophosphate-lyase (cyclizing)8 EC 4.6.1.1] in the pineal gland are similar to the properties of the sites which specifically bind l-[3H]alprenolol, a potent beta-adrenergic antagonist. Stimulation of the beta-adrenergic receptor results in a 30-fold increase in the activity of N-acetyltransferase (= arylamine acetyltransferase; acetyl CoA:arylamine N-acetyltransferase, EC 2.3.1.5), an enzyme involved in the synthesis of thepineal hormone melatonin. In the normal diurnal light-dark cycle there is greater physiological stimulation of the beta-adrenergic receptor in the pineal during the night than during the day. Pineals from rats kept in constant light for 24 hr possess more hormone-sensitive adenylate cyclase and specifically bind more l-[3H]alprenolol than do pineals from rats kept in the dark overnight. When rats, exposed to light for 24 hr, are treated with the beat-adrenergic agonist isoproterenol, there is a rapid loss of both hormone-sensitive adenylate cyclase activity and specific l-[3H]alprenolol binding sites. There is no change in the affinity of adenylate cyclase for isoproterenol or for its substrate, ATP. Similarly, although there are fewer binding sites, there is no change in the affinity of the remaining sites for either agonist or antagonist. Inhibition of protein synthesis with cycloheximide does not affect the loss of either adenylate cyclase activity or specific binding sites. The data suggest that stimulation of the beta-adrenergic receptor causes a rapid decrease in the number of available receptors and in hormone-sensitive adenylate cyclase activity; conversely, lack of stimulation causes an increase in these parameters. It is suggested that these changes contribute to the phenomena of super- and subsensitivity in the pineal gland by regulating the capacity of the pineal to synthesize cyclic AMP in response to beta-adrenergic stimulation.

Adenosine Triphosphate↗