Catecholamine-Sensitive Adenylate Cyclase in the White Perch (Roccus americanus) Retina: Evidence for β-Adrenergic and Dopamine Receptors Linked to Adenylate Cyclase

We have examined the catecholamine-sensitive adenylate cyclase in the retina of the white perch (Roccus americanus). Both dopamine and the beta-adrenergic agonist isoproterenol stimulate cyclic AMP accumulation in this retina, but serotonin, an indoleamine, and phenylephrine, an alpha-adrenergic agonist, had no effect. The stimulation of adenylate cyclase by isoproterenol is more potent and effective than that of dopamine. The effects of dopamine and isoproterenol are mediated via independent dopamine and beta-adrenergic receptors. Haloperidol, a dopamine antagonist, blocks the stimulatory effect of dopamine but not of isoproterenol. Conversely, propranolol, a beta-adrenergic antagonist, blocks the stimulatory effect of isoproterenol but not of dopamine. The effects of dopamine and isoproterenol are not additive. In fractions of purified horizontal cells we found evidence for dopamine receptors linked to adenylate cyclase but did not find evidence for the presence of cyclase coupled beta-adrenergic receptors. The cellular location of the beta-adrenergic receptors is unknown. Our findings demonstrate the existence of both beta-adrenergic and dopamine receptors coupled to adenylate cyclase in the white perch retina. However, we did not find either epinephrine or norepinephrine, endogenous ligands of the beta-receptor, to be present in retinal extracts subjected to HPLC.     

Pharmacological characterization of the dopamine-mediated accumulation of cyclic AMP in intact retina of rabbit.

Exposure of intact retinae of rabbit to dopamine, epinephrine and norepinephrine led to dose-related accumulations of cyclic AMP. Dopamine appears to be more potent than the two other catecholamines, since at 10^?6M it still induced a significant increase in cyclic AMP, whereas the two latter drugs were ineffective. Pure α- or β-adrenergic agonists such as phenylephrine or isoproterenol, as well as other drugs such as clonidine, DPI, (+)- and (±)-amphetamine, used at 10^?4M, were also devoid of agonist activity. In contrast a dopamine-analogue (epinine) and a dopamine-like drug (apomorphine) were as potent as dopamine. Blockade of the dopamine- or norepinephrine-elicited accumulation of cyclic AMP was achieved by antipsychotics such as fluphenazine, (+)-butaclamol and lithium, whereas propranolol (a β-adrenergic antagonist), phentolamine (an α-adrenergic antagonist) and (?)-butaclamol (an inactive compound), at 10^?4 to 5 × 10^?4M concentrations, showed no antagonist activity. The results indicate that the cyclic AMP production induced by catecholamines in intact retina of rabbit is a result of an activation of relatively pure dopamine receptors.     

Multiple Adrenergic Receptor Subtypes Controlling Cyclic AMP Formation: Comparison of Brain Slices and Primary Neuronal and Glial Cultures

The adrenergic receptor subtypes involved in cyclic AMP responses to norepinephrine (NE) were compared between slices of rat cerebral cortex and primary neuronal and glial cultures from rat brain. In neuronal cultures, NE and the beta-adrenergic receptor agonist isoproterenol (ISO) caused similar increases in cyclic AMP, which were not altered by the alpha-adrenergic receptor antagonist phentolamine. In glial cultures, NE caused a much smaller cyclic AMP response than did ISO, and this difference was reversed by alpha-adrenergic receptor antagonists (phentolamine greater than yohimbine greater than prazosin). alpha 2-Adrenergic receptor agonists partially inhibited the ISO response in glial cultures to a level similar to that observed with NE alone (clonidine = UK 14,304 greater than NE greater than 6-fluoro-NE greater than epinephrine). In slices from cerebral cortex, NE caused a much larger increase in cyclic AMP than did ISO, and this difference was reversed by alpha-adrenergic receptor antagonists with a different order of potency (prazosin greater than phentolamine greater than yohimbine). alpha 1-Adrenergic receptor agonists potentiated the response to ISO to a level similar to that observed with NE alone (epinephrine = NE greater than phenylephrine greater than 6-fluoro-NE greater than methoxamine). In all three tissue preparations, large responses to both alpha 1-receptor activation (increases in inositol phosphate accumulation) and alpha 2-receptor activation (decreases in forskolin-stimulated cyclic AMP accumulation) were observed. These data indicate that all of the major adrenergic receptor subtypes (beta, alpha 1, alpha 2) are present in each tissue preparation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mediation of Norepinephrine-Stimulated Cyclic AMP Accumulation by Adrenergic Receptors in Hypothalamic and Preoptic Area Slices: Effects of Estradiol

Adrenergic receptor agonists and antagonists were employed to establish (a) which receptor subtypes mediate the cyclic AMP response to norepinephrine in hypothalamic and preoptic area slices from gonadectomized female rats and (b) which receptor subtypes might be modulated by the steroid hormone estradiol. Slice cyclic AMP levels were elevated by the beta receptor agonist isoproterenol, but not by alpha 1 (phenylephrine, methoxamine) or alpha 2 (clonidine) agonists. However, the alpha agonist phenylephrine potentiated the effect of the beta agonist isoproterenol on slice cyclic AMP accumulation. In slices from rats given no hormone treatment, the beta antagonist propranolol inhibited norepinephrine-stimulated cyclic AMP production, while the alpha 1 antagonist prazosin was without effect. In contrast, the cyclic AMP response to norepinephrine in slices from estradiol-treated rats was blocked more effectively by prazosin than by propranolol. Estradiol treatment also attenuated the production of cyclic AMP by the beta agonist isoproterenol. The data suggest (a) that norepinephrine induction of cyclic AMP accumulation in hypothalamic and preoptic area slices is mediated by beta receptors and potentiated by alpha receptor activation and (b) that estradiol depresses beta and increases alpha 1 receptor function in slices from brain regions associated with reproductive physiology.     

In Vivo Evidence that Nonneuronal β-Adrenoceptors as Well as Dopamine Receptors Contribute to Cyclic AMP Efflux in Rat Striatum

Abstract: We applied in vivo microdialysis to assess the effects of dopaminergic and β-adrenergic receptor stimulation on cyclic AMP efflux in rat striatum under chloral hydrate anesthesia. Dopamine (up to 1 mM) infused for 20 min through the probe did not increase cyclic AMP, whereas both the selective dopamine D₁ agonist SKF 38393 and D₂ antagonist sulpiride produced modest increases. It is interesting that the β-adrenoceptor agonist isoproterenol produced a marked increase (204.7% of basal level at 1 mM) which was antagonized by the β-adreno-ceptor antagonist propranolol. Pretreatment with a glial selective metabolic inhibitor, fluorocitrate (1 mM), by a 5-h infusion through the probe attenuated basal cyclic AMP efflux by 30.3% and significantly blocked the response to isoproterenol. By contrast, striatal injection of a neuro-toxin, kainic acid (2.5 μg), 2 days before the dialysis experiment did not affect basal cyclic AMP or the response to isoproterenol, but blocked the response to SKF 38393. These data demonstrate that β-adrenoceptors as well as dopamine receptors contribute to cyclic AMP efflux in rat striatum in vivo. They also suggest that basal and β-adre-noceptor-stimulated cyclic AMP efflux are substantially dependent on intact glial cells.     

Effect of adrenergic agents on alpha-amylase release and adenosine 3',5'-monophosphate accumulation in rat parotid tissue slices.

The role of cyclic AMP in stimulus-secretion coupling with investigated in rat parotid tissue slices in vitro. Isoproterenol and norepinephrine stimulated a rapid intracellular accumulation of cyclic AMP, which reached a maximum level of 20-30 times the control value by 5 to 10 min after addition of the drug. Isoproterenol was approximately ten times more potent in stimulating both alpha-amylase release and cyclic AMP accumulation than were norepinephrine and epinephrine, which had nearly equal effects on these two parameters. Salbutamol and phenylephrine were less effectivema parallel order of potency and sensitivity was observed for the stimulation of adenylate cyclase activity in a washed particulate fractionmthe results suggest that these drugs are acting on a parotid acinar cell through a beta1-adrenergic mechanismmat the lowest concentrations tested, each of the adrenergic agonists stimulated significant alpha-anylase release with no detectable stimulation of cyclic AMP accumulationmeven in the presence of theophylline, phenylephrine at several concentrations increased alpha-amylase release without a detectable increase in cyclic AMP levels. However, phenylephrine did stimulate adenylate cyclase. These data suggest that, under certain conditions, large increases in the intra-cellular concentration of cyclic AMP may not be necessary for stimulation of alpha-amylase release by adrenergic agonists. Also consistent with this idea was the observation that stimulation of cyclic AMP accumulation by isoproterenol was much more sensitive to inhibition by propranolol than was the stimulation of alpha-amylase release by isoproterenol. Stimulation of alpha-amylase release by phenylephrine was only partially blocked by either alpha- or beta-adrenergic blocking agents, whereas stimulation of adenylate cyclase by phenylephrine was blocked by propranolol and not by phentolaminemphenoxybenzamine and phentolamine potentiated the effects of norepinephrine and isoproterenol on both cyclic AMP accumulation and alpha-amylase release by N-6,O-2'-dibutyryl adenosine 3',5'-monophosphate; These observations may indicate a non-specific action of phenoxybenzamine, and demonstrate the need for caution in interpreting evidence obtained using alpha-adrenergic blocking agents as tools for investigation of alpha- and beta-adrenergic antagonism.     

Effects of isoproterenol on cyclic-AMP metabolism in rat ventral prostate.

Beta-Adrenergic stimulation of the ventral prostate cyclic-AMP system was investigated by examining the influence of isoproterenol on endogenous cyclic-AMP levels as well as on the activities of adenylate cyclase CEC 4.6.1.1) and cyclic-AMP-dependent and independent protein kinases (EC 2.7.1.37). Administration of isoproterenol (1 mg/kg, ip) resulted in rapid elevation of adenylate cyclase activity (119%) and cyclic-AMP levels (593%). The observed isoproterenol-stimulated changes in cyclic-AMP metabolism of the ventral prostate were time-dependent and maximal stimulation was seen 5 min after treatment with this beta-adrenergic agonist. The increases in prostatic adenylate cyclase and cyclic-AMP also were related to the dose of isoproterenol administered and maximal enhancement of these parameters was seen with 1 mg/kg dose of the agonist. Whereas pretreatment of rats with propranolol (3mg/kg, ip) partially reversed these alterations, administration of an alpha-adrenergic antagonist, phentolamine, even at a dose of 5 mg/kg, failed to elicit any appreciable effect. Stimulation of prostatic soluble protein kinase by isoproterenol was associated with a decrease (33%) in the activity of the cyclic-AMP-dependent protein kinase with a concomitant increase (25%) in that of the independent enzyme. Whereas the ability of the enzyme to bind cyclic-(3H) AMP in vitro was decreased (54%) following isoproterenol treatment, the protein kinase activity ratio (-cyclic-AMP/+cyclic AMP) was significantly elevated from 0.51+/0.05 to 0.95+/0.08. Although propranolol alone had little or no effect on these parameters, it inhibited partially the isoproterenol-induced alterations in cyclic-AMP-dependent protein kinase and the cyclic-AMP binding capacity. Treatment with propranolol also blocked the increases in the kinase activity ratio and in the activity of cyclic-AMP-independent enzyme seen with isoproterenol. Data suggest that the concentration of ventral prostate cyclic-AMP as well as the activities of adenylate cyclase and cyclic-AMP-dependent and independent form of protein kinases are subject to modulation by beta-adrenergic stimulation.     

Effects of biogenic amines on the formation of adenosine 3',5'-monophosphate in human thyroid slices.

The effects of various concentrations of biogenic amines on the formation of adenosine-3', 5'-monophosphate (cyclic AMP) and their interactions with other thyroid stimulators were investigated in human thyroid slices from normal and Graves' disease. Most of biogenic amines were found to have the stimulatory effects to some extent. Among the biogenic amines tested, histamine was the most potent thyroid stimulator, norepinephrine and serotonin, the intermediate in terms of cyclic AMP formation. The effect of histamine was almost as potent as TSH in thyroid slices from Graves' disease. This stimulatory effect of histamine was blocked by metiamide, a histamine H2-receptor antagonist, but not by chlorpheniramine, a histamine H1-receptor antagonist. The effect of norepinephrine was completely inhibited by propranolol, but not by phentolamine. Polyphloretin phosphate did not inhibit norepinephrine- or histamine-induced cyclic AMP formation, while it significantly depressed cyclic AMP formation induced by prostaglandin E2. The maximal effect of histamine was additive to that of TSH. It is suggested that biogenic amines, histamine and norepinephrine, in particular, have the thyroid receptors different from that of TSH or prostaglandin E2 and could play an important role in thyroid physiology.     

Effects of biogenic amines on the formation of adenosine 3', 5'-monophosphate in human thyroid slices.

The effects of various concentrations of biogenic amines on the formation of adenosine-3', 5'-monophosphate (cyclic AMP) and their interactions with other thyroid stimulators were investigated in human thyroid slices from normal and Graves' disease. Most of biogenic amines were found to have the stimulatory effects to some extent. Among the biogenic amines tested, histamine was the most potent thyroid stimulator, norepinephrine and serotonin, the intermediate in terms of cyclic AMP formation. The effect of histamine was almost as potent as TSH in thyroid slices from Graves' disease. This stimulatory effect of histamine was blocked by metiamide, a histamine H2-receptor antagonist, but not by chlorpheniramine, a histamine H1-receptor antagonist. The effect of norepinephrine was completely inhibitied by propranolol, but not by phentolamine. Polyphloretin phosphate did not inhibit norepinephrine- or histamine-induced cyclic AMP formation, while it significantly depressed cyclic AMP formation induced by prostaglandin E2. The maximal effect of histamine was additive to that of TSH. It is suggested that biogenic amines, histamine and norepinephrine, in particular, have the thyroid receptors different from that of TSH or prostaglandin E2 and could play an important role in thyroid physiology.     

Hormonal stimulation of cyclic AMP accumulation and glycogen phosphorylase activity in calcium-depleted hepatocytes from euthyroid and hypothyroid rats.

Activation of glycogen phosphorylase by hormones was examined in hepatocytes isolated from euthyroid and hypothyroid female rats and incubated by Ca2+-free buffer containing 1 mM-EGTA. Basal glycogen phosphorylase activity was decreased in Ca2+-free buffer. However, the activation of hepatocyte glycogen phosphorylase, in the absence of extracellular Ca2+, in response to adrenaline, glucagon or phenylephrine was slightly lower, whereas that by vasopressin was abolished. The activation of glycogen phosphorylase by phenylephrine, adrenaline or isoproterenol (isoprenaline) in hepatocytes from euthyroid rats incubated in the absence of Ca2+ was not accompanied by any detectable increase in total cyclic AMP. The log-dose/response curves for activation of phosphorylase by phenylephrine or low concentrations of adrenaline were the same in hepatocytes from hypothyroid as compared wit euthyroid rats, whereas the response to isoproterenol was greater in hepatocytes from hypothyroid rats. However, the increases in total cyclic AMP accumulation caused by adrenaline or isoproterenol were greater in hepatocytes from hypothyroid rats than in hepatocytes from euthyroid rats. The increases in cyclic AMP accumulation caused by adrenaline or isoproterenol in Ca2+-depleted hepatocytes from hypothyroid rats were blocked by propranolol, a beta-adrenergic antagonist. In contrast, propranolol was only partially effective asan inhibitor of the activation of glycogen phosphorylase by phenylephrine or adrenaline in hepatocytes from hypothyroid rats and ineffective on phosphorylase activation in cells from euthyroid rats. These data indicate that the alpha-adrenergic activation of glycogen phosphorylase is not affected by the absence of extracellular Ca2+, and the extent to which total cyclic AMP was increased by adrenergic amines did not correlate with glycogen phosphorylase activation.     

Effects of catecholamines on ammoniagenesis and gluconeogenesis by renal cortex in vitro

Norepinephrine (arterenol) and a synthetic catecholamine, isoproterenol, increase the production of ammonia and glucose from glutamine and glutamate by rat renal cortical slices in vitro. The stimulation of both ammonia and glucose production by isoproterenol was greater than that observed with identical molar concentrations of arterenol. Isoproterenol markedly increased the concentration of cyclic AMP in rat renal cortical slices. Addition of propranolol, a β-adrenergic blocking agent, prevented the increase of cyclic AMP levels induced by isoproterenol. Cyclic AMP increased both ammoniagenesis and gluconeogenesis by kidney cortex. Thehe increase in ammonia production produced by isoprotenol was blocked by the addition of propranolol. It is concluded that the increase in ammonia and glucose production caused by isoproterenol is mediated through the release of cyclic AMP.     

Adrenergic modulation of insulin and glucagon secretion from the isolated perfused rat pancreas

In order to observe the effect of the adrenergic system on pancreatic glucagon secretion in the isolated perfused rat pancreas, phenylephrine, an alpha-adrenergic agonist, and isoproterenol, a beta-adrenergic agonist, were added to the perfused solution. 1.2 microM phenylephrine suppressed glucagon secretion at 2.8 mM glucose, and it also decreased insulin secretion at 11.1 mM glucose. 240 nM isoproterenol enhanced glucagon secretion not only at 2.8 mM glucose, but also at 11.1 mM glucose, as well as insulin secretion at 11.1 mM. In order to study the role of intra-islet noradrenalin, phentolamine, an alpha-adrenergic antagonist, and propranolol, a beta-adrenergic antagonist, were infused with the perfused solution. 10 and 100 microM phentolamine caused an increase in insulin secretion, and 25 microM propranolol decreased insulin secretion, while they did not cause any change in glucagon secretion. From these results, it can be concluded that alpha-stimulation suppresses not only insulin but also glucagon secretion, while beta-stimulation stimulates glucagon secretion, as well as insulin secretion. Intra-islet catecholamine may have some effect on the B cell, whereas it seems to have no influence on the A cell.     

Dopamine- and octopamine-sensitive adenylate cyclase in the brain of adultCulex pipiens mosquitoes

The effects of dopamine and octopamine on adenylate cyclase activity were studied on the head homogenate of adult Culex pipiens mosquitoes in vitro. Both dopamine and octopamine were shown to increase the cyclic AMP content in the homogenate. The antagonist haloperidol blocked the production of cyclic AMP induced from dopamine but had no effect on the production of cyclic AMP induced by octopamine at the concentrations tested. The opiate agonist etorphine was ineffective at reducing cyclic AMP levels induced by either dopamine or octopamine at the concentrations tested.     

Serotonergic modulation of footshock induced aggression in paired rats.

Footshock induced aggression (FIA) was induced in paired rats and three paradigms of aggressive behaviour were recorded, namely, latency to fight (LF), total period of physical contact (TPP) and cumulative aggression scores (CAS). The effects of increasing or decreasing central serotonergic activity, by using a number of pharmacological agents with well defined effects on rat brain serotonin, were investigated on FIA and on FIA augmented by apomorphine, a dopamine receptor agonist. The results show that centrally administered serotonin, the serotonin precursor, 5-hydroxytryptophan administered with clorgyline, a selective MAO A inhibitor, quipazine, a serotonin receptor agonist, and fluoxetine, a selective inhibitor of neuronal re-uptake of serotonin, attenuated all paradigms of FIA and apomorphine induced potentiation of FIA. On the contrary, the other re-uptake inhibitor used, citalopram, appeared to have a dual effect and decreased LF and CAS, while increasing TPP. The serotonin synthesis inhibitor, p-chlorophenylalanine and the selective serotonin receptor (5-HT2) antagonist, ketanserin, augmented all paradigms of FIA per se and apomorphine induced augmentation of FIA. However, the other serotonin receptor antagonist used, metergoline, which blocks both 5-HT1 and 5-HT2 receptor subtypes, attenuated FIA per se but decreased only CAS in apomorphine induced increase in FIA. The data confirm the inhibitory effect of the central serotonergic system on aggressive behaviour and the inverse relationship existing between it and the central dopaminergic system in the modulation of FIA, as has also been confirmed in earlier biochemical investigations from this laboratory. The data has been discussed in the light of existing knowledge on serotonin receptor subtypes and the presence of modulatory serotonergic heteroreceptors on central dopaminergic neurones.     

[3H]GLYCOGEN HYDROLYSIS IN BRAIN SLICES: RESPONSES TO NEUROTRANSMITTERS AND MODULATION OF NORADRENALINE RECEPTORS

Abstract— Different agents have been investigated for their effects on [C³H]glycogen synthesized in mouse cortical slices. Of these noradrenaline, serotonin and histamine induced clear concentration-dependent glycogenolysis.
[C³H]Glycogen hydrolysis induced by noradrenaline appears to be mediated by beta-adrenergic receptors because it is completely prevented by timolol, while phentolamine is ineffective. It seems to involve cyclic AMP because it is potentiated in the presence of isobutylmethylxanthine; in addition dibutyryl cyclic AMP (but not dibutyryl cyclic GMP) promotes glycogenolysis.
Lower concentrations of noradrenaline were necessary for [C³H]glycogen hydrolysis (EC₅₀= 0.5μM) than for stimulation of cyclic AMP accumulation (EC₅₀= 8μM).
After subchronic reserpine treatment the concentration-response curve to noradrenaline was significantly shifted to the left (EC₅₀= 0.09 ± 0.02 μM as compared with 0.49 ± 0.08 μM in saline-pretreated mice) without modifications of either the basal [C³H]glycogen level, maximal glycogenolytic effect, or the dibutyryl cAMP-induced glycogenolytic response.
In addition to noradrenaline, clear concentration-dependent [³H]glycogen hydrolysis was observed in the presence of histamine or serotonin. In contrast to the partial [³H]glycogen hydrolysis elicited by these biogenic amines, depolarization of the slices by 50 mM K⁺ provoked a nearly total [C³H)glycogen hydrolysis.     

Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist

The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by gamma-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for 3H-dopamine and 3H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs.     

Adrenergic control of lipogenesis and lipolysis in the chicken in vitro

The adrenergic inhibition of lipogenesis and stimulation of lipolysis in the avian has been examined using chicken hepatocytes and adipose tissue explants in vitro. Lipogenesis was inhibited by adrenergic agonists: epinephrine (alpha + beta) greater than isoproterenol (beta 1/beta 2) greater than norepinephrine (alpha 1/alpha 2, beta 1) greater than metaproterenol (beta 2), phenylephrine (alpha 1). Dobutamine (beta 1 agonist) and dopamine (dopaminergic agonist) did not significantly affect [14C]acetate incorporation into lipid, while clonidine and para-aminoclonidine (alpha 2 agonists) were slightly stimulatory. Lipolysis in young and adult chicken adipose tissue was stimulated by epinephrine, isoproterenol, phenylephrine, dobutamine and metaproterenol, but was inhibited by clonidine and para-aminoclonidine. Both the antilipogenic and lipolytic effects of epinephrine were partially blocked by phentolamine (alpha 1 = alpha 2 antagonist) or propranolol (beta 1 = beta 2 antagonist), but completely inhibited by phentolamine and propranolol administered together.     

Regulation of protein synthesis in intact rat liver by calcium mobilizing agents

1. Exposure of intact perfused rat liver to EGTA, vasopressin or phenylephrine resulted in a rapid decrease in polysome formation. Pretreatment with phentolamine, an alpha-adrenergic antagonist, blocked the effect of phenylephrine. 2. Hormonal inhibitions of leucine incorporation into protein in isolated hepatocytes and of polysome formation in perfused liver were reversed in the presence of supraphysiologic extracellular Ca2+ concentrations. 3. The beta-adrenergic agonist isoproterenol exerted minimal effects on polysome content. 4. It is proposed that intracellular Ca2+ stores sensitive to hormonal modulation are necessary for maintenance of protein synthesis in hepatocytes.     

Modulatory effects of catecholamines on neurons of the rat visual cortex: single-cell iontophoretic studies

The catecholamines noradrenaline and dopamine have been proposed as neuromodulators of cortical neuron excitability, and such a regulation could be mediated by specific adrenergic and dopaminergic receptors. We characterized electrophysiologically some of the types of responses to the iontophoretic application of adrenergic and dopaminergic agonists and antagonists on single cells in the rat visual cortex (areas occipital 1 monocular or Oc1M and occipital 1 binocular or Oc1B). For the majority of spontaneously active and visual cortical cells, noradrenaline and dopamine decreased the firing frequency. In the case of visually driven (synaptically activated) neurons, background firing was the main component of the response to be inhibited by the administration of noradrenaline, clonidine, and oxymetazoline, leading to an enhancement of the signal-to-noise ratio. Since these effects could be reduced or blocked by a previous ejection of the specific alpha 2-antagonist idazoxan, the findings support a role for alpha 2-adrenergic receptors in the transmission of sensory inputs to the visual cortex. These effects were not found with the mixed alpha-adrenergic agonist phenylephrine nor with the beta-agonist isoproterenol. Finally, the use of the inhibitory amino acid GABA rules out a simple hyperpolarizing response as the mechanism underlying noradrenaline modulatory effects in the cerebral cortex.     

Isoproterenol and insulin control the cellular localization of ATP citrate-lyase through its phosphorylation in adipocytes

The enzyme ATP citrate-lyase of the fatty acid synthesis pathway is phosphorylated in vitro and in isolated cells. However, no effect of phosphorylation on the enzyme activity has been detected. It is demonstrated that the beta-adrenergic agonist isoproterenol or insulin both promote an immobilization of ATP citrate-lyase, detected in digitonin-permeabilized adipocytes. This effect was reproduced by the cyclic AMP analog cyclic 8-bromo-AMP. The beta-adrenergic antagonist propranolol blocked, but failed to reverse, the isoproterenol-directed effect. Propranolol also failed to reverse the isoproterenol-induced increased phosphorylation of ATP citrate-lyase specifically. In response to increasing concentrations of isoproterenol, an increased extent of phosphorylation of ATP citrate-lyase was paralleled by an increased immobilization of the enzyme. It is suggested that the state of phosphorylation of ATP citrate-lyase in adipocytes controls the localization in the cell.