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Biomedical subjects

A Guidotti

Publications and source records attributed to A Guidotti.

At least 271 records · Page 15Linked to original sources
PubMed1977

Endogenous protein kinase inhibitors. Purification, characterization, and distribution in different tissues.

A thermostable inhibition of ATP-protein phosphotransferase (EC 2.7.1.37) (protein kinase) which is present in crude tissue extracts has been resolved by gel chromatography (Sephadex G-100) into two molecular forms. These two forms will be referred to as type I and type II inhibitor. The type I inhibitor (Mr approximately or equal to 24,000) is specific for cAMP-dependent protein kinase and corresponds to the inhibitor described earlier (Walsh, D. A., Ashby, C. D., Gonzalez, C., Calkins, D., Fisher, E. H., and Krebs, E. G. (1971) J. Biol. Chem. 246, 1977-1985). The type II inhibitor (Mr approximately or equal to 15,000) competes for the enzyme with various substrate proteins (histone, alpha-casein, and Leu-Arg-Arg-Ala-Ser-Leu-Gly (kemptide). The type II inhibitor blocks protein phosphorylation catalyzed by several types of protein kinases (cAMP- and cGMP-dependent or cyclic nucleotide-independent protein kinases). The type II inhibitor from rat brain has been purified 1500-fold; this protein is thermostable, has acidic characteristics, and does not require Ca2+ ions for its activity. Different ratios and concentrations of type I and type II inhibitors of protein kinase are found in rat skeletal muscle, pancreas, cerebellum and corpus striatum, and in lobster tail muscle.

Animals↗
PubMed1977

Dopamine-sensitive adenylate cyclase: location in substantia nigra.

A dopamine-sensitive adenylate cyclase with characteristics similar to those measured in the striatum is present in the rat substantia nigra. Destruction of dopamine cell bodies by intranigral 6-hydroxydopamine application failed to abolish the response of nigral adenylate cyclase to dopamine. In contrast, brain hemitransection between the striatum and substantia nigra, or a more circumscribed lesion of striatonigral pathways, abolished the dopamine stimulation of adenylate cyclase in the substantia nigra. These results suggest that dopamine receptors within the substantia nigra are not located on dopamine cell bodies but are associated with a pathway, containing gamma-aminobutyric acid or substance P, which projects from forebrain structures to the substantia nigra.

Adenylyl Cyclases↗
PubMed1977

On the mechanism of the decrease in cerebellar cyclic GMP content elicited by opiate receptor agonists.

Morphine, dextromoramide (4 mumol/kg i.p.) and vimonol R2 (17 mumol/kg i.p.) in analgesic doses (28 to 112 mumol/kg i.p.) decreased 3',5'-cyclic guanosine monophosphate (cGMP) in rat cerebellar cortex; morphine also decreased the cGMP content in deep cerebellar nuclei. Intrastriatal but not intracerebellar injections of morphine (20 mug) decreased cerebellar cGMP content. Naltrexone, an opiate receptor antagonist, but only apomorphine, a dopaminergic receptor agonist, blocked the effect of morphine on cerebellar cGMP. Pretreatment with 3-acetylpyridine (3-AP) which destroys the climbing fibers, failed to antagonize the effect of morphine on cerebellar cGMP. These results suggest that activation of opiate receptors in striatum decreases cerebellar cGMP content presumably by reducing activity in the mossy fiber excitatory input to cerebellum.

Analgesics↗
PubMed1977

Mechanisms by which diazepam, muscimol, and other drugs change the content of cGMP in cerebellar cortex.

THE CEREBELLUM CONSISTS OF TWO PARTS: the cerebellar nuclei whose connections to the various parts of the central nervous system coordinate muscle movements, and the cerebellar cortex which exerts an inhibitory influence on the cerebellar nuclei through the release of gamma-aminobutyric acid (gammaAbu) from Purkinje cells. The activity of Purkinje cells is regulated by two excitatory inputs to the cerebellar cortex-the climbing and mossy fibers-and by a neuronal network within the cortex which inhibits the activity of Purkinje cells through the release of gammaAbu from interneurons. The net activity of Purkinje cells is related to their content of guanosine 3':5'-cyclic monophosphate (cGMP) which increases or decreases according to changes in the activity of climbing and mossy fibers as well as to changes in the activation of gammaAbu receptors. When these receptors are activated, the cGMP of Purkinje cells decreases; when they are inhibited, the cGMP increases.The cGMP content of the cerebellar cortex is altered by drugs that change either the excitatory input of climbing or mossy fibers or the inhibitory input mediated by the activation of gammaAbu receptors. Mechanisms by which various drugs alter the cerebellar content of cGMP were investigated. By using various experimental designs, it was shown that diazepam and muscimol lowered the cGMP content by activating gammaAbu receptors. In contrast, morphine and haloperidol lowered the cerebellar cortex cGMP by decreasing the excitation of mossy fibers whereas harmaline increased the cGMP by increasing the excitation of the climbing fibers.

Alkaloids↗
PubMed1977

Pharmacologically induced changes in the 3':5'-cyclic guanosine monophosphate content of rat cerebellar cortex: difference between apomorphine, haloperidol and harmaline.

Harmaline increases cerebellar 3':5'-cyclic guanosine monophosphate (cGMP) content in a dose-related manner; this increase is prevented by a pretreatment with 3-acetylpyridine (3-AP) (0.66 mmol/kg) which destroys climbing fibers and inhibits harmaline-induced tremor. The cerebellar cGMP content increases after isoniazid; this response remains unchanged in rats pretreated with 3-AP. Since isoniazid decreases cerebellar gamma-aminobuturic acid (GABA) levels, the increase in cGMP content might reflect a reduction in the availability of GABA at the level of postsynaptic receptors. Apomorphine (a dopamine receptor agonist) and haloperidol (a dopamine receptor blocker) increase or decrease the cGMP content of cerebellar cortex, respectively. Neither drug changes the guanylate cyclase activity of cerebellar homogenates; moreover their action on cerebellar cGMP content persists after 3-AP. Chloropromazine, like haloperidol, decreases the cerebellar cGMP content. The increase in cerebellar cGMP content elicited by apomorphine can be differentiated from that elicited by harmaline or isoniazid; presumably apomorphine indirectly activates mossy fibers. The decrease in cerebellar cGMP content elicited by haloperidol can be differentiated from that elicited by diazepam; perhaps haloperidol reduces the mossy fiber input to the cerebellum. We suggest that the cGMP content of cerebellar cortex fluctuates in response to changes in the afferent stimulatory input to the cerebellum; it increases when the activity of either climbing or mossy fibers is increased; it decreases when either of these two stimulatory inputs is reduced.

Alkaloids↗
PubMed1976

Induction of tyrosine 3-monooxygenase in adrenal medulla: role of protein kinase activation and translocation.

The transsynaptic induction of tyrosine 3-monooxygenase (TH) in rat adrenal medulla is preceded by an early increase in the ratio of cyclic adenosine monophosphate (AMP) to cyclic guanosine monophosphate, an activation of cytosol cyclic AMP-dependent protein kinase, and a subsequent translocation of protein kinase catalytic subunits from cytosol to subcellular particles. As a result of this translocation, nuclear protein kinase activity increases during the induction of TH. Transection of splanchnic nerve reverts these events and prevents the induction of TH. Thus, adrenal medulla activation and translocation of cyclic AMP-dependent protein kinase may act as a long-range messenger for the genetic regulation of TH synthesis.

Adrenal Medulla↗
PubMed1976

Climbing fiver activation and 3', 5'-cyclic guanosine monophosphate (cGMP) content in cortex and deep nuclei of cerebellum.

Harmaline (28 mumoles/kg u.v.), cold exposure (4C) or isoniazid (2.2 mmoles/kg s.c.) increased the cGMP content in rat cerebellar cortex several fold. Isoniazid but not harmaline or cold exposure increased cGMP in the deep cerebellar nuclei (nuclei interpositus, vestibularis and fastigius) and striatum. In rats treated with the nicotinamide antagonist 3-acetylpyridine (3-AP) (0.66 mumoles/kg i.p. 4 days before) the tremorogenic effect of harmaline and the increase of cerebellar cortex cGMP produced by this alkaloid was abated. Similarly the increase of cGMP following exposure to cold was reduced. In contrast isoniazid and glutamate (10 mumoles intraventricularly) increased cGMP to the same extent in control and 3-AP treated rats. Since 3-AP produces in rat a massive degeneration of the inferior olivary nucleus and of the climbing fibers but leaves intact all the other cerebellar elements, these experiments suggest that an increase of cGMP content in postsynaptic cerebellar elements (presumable Purkinje cells) may be an expression of an increased release of an excitatory transmitter from either the climbing fivers or the parallel fibers.

Animals↗
PubMed1976

Association between the increase of cAMP content and the trans-synaptic induction of tyrosine hydroxylase in rat adrenal medulla. Studies with dexamethasone and reserpine.

When dexamethasone 0.25 or 2.5 mumole/kg i.p. was injected 2 h before reserpine (16 mumol/kg i.p.) the time course of the increase in cAMP content of rat adrenal medulla was changed. Reserpine alone caused a monophasic increase lasting between 1-2 h; reserpine after dexamethasone caused a biphasic increase: the immediate response, lasting between 15 and 30 min, was followed by a secondary increase beginning 2-3 h after reserpine and lasting for several hours. The overall increase in cAMP content elicited by reserpine during the 8 h following injection remained unchanged or was even increased, depending on the dose of dexamethasone. Pretreatment with dexamethasone, which delayed the increase in cAMP, also delayed the activation and translocation of protein kinase and the induction of tyrosine hydroxylase caused by reserpine in adrenal medulla. The action of reserpine on the cAMP content of adrenal medulla required an intact innervation and did not appear to be related to increased secretion of ACTH from pituitary. In denervated adrenals reserpine failed to increase the cAMP content of the medulla but not that of the cortex.

Adrenal Cortex↗
PubMed1976

Activation and nuclear translocation of protein kinase during transsynaptic induction of tyrosine 3-monooxygenase.

The tyrosine-3-monooxygenase activity [L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating); EC 1.14.16.2] of rat adrenal medulla is induced 20-24 hr after the injection of reserpine (16 mumol/kg intraperitoneally). This and other inducing stimuli increase the 3': 5'-cyclic AMP (cAMP) content in the medulla for longer than 60 min and activate the cAMP-dependent protein kinase (ATP: protein phosphotransferase; EC 2.7.1.37) for several hours. Corticotropin (ACTH), dopamine, and propranolol do not induce the monooxygenase, but elicit an increase in the cAMP content of the medulla which fails to activate protein kinase and lasts less than 1 hr. A high- and low-molecular-weight protein kinase are separated by gel filtration from the 20,000 X g pellet extract of adrenal medulla homogenate. The activity of the low-molecular-weight enzyme is expressed as its ability to phosphorylate histone. The protein kinase activity of the pellet is increased between 3 and 17 hr after reserpine injection. Our evidence indicates that this increase is due to a translocation from cytosol to subcellular structures of a kinase that utilizes lysine-rich histone as phosphate acceptor. The protein kinase activity that is extracted from a purified nuclear fraction prepared from the adrenal medulla of rats injected 7 hr previously with reserpine is greater than that extracted from medulla of saline-treated rats.

Adrenal Medulla↗