Meningiomas are tumours derived from the arachnoid and pia mater. During embryogenesis, these mem... more Meningiomas are tumours derived from the arachnoid and pia mater. During embryogenesis, these membranes develop from the migrating craniofacial neural crest. We have previously demonstrated that meningiomas have characteristic features of embryonic meninges. Craniofacial neural crest derivatives are affected during normal development and migration by retinoic acid. We speculated, therefore, that meningioma cell migration and invasion would be affected in a similar way. In this study we investigated the mechanisms of invasion and migration in meningiomas and the effects of retinoic acid (RA). We found that low doses of RA inhibit in vitro invasion in meningioma cells, without affecting cell proliferation or viability. The matrix metalloproteinases MMP-2 (72 kDa gelatinase) and MMP-9 (92 kDa gelatinase), which play a key role in invasion in other tumours, are not affected by RA. RA inhibits cell migration on collagen I and fibronectin. A possible mechanism for these effects is provide...
Chromaffin cells and sympathetic neurons arise from a common bipotential progenitor which, if exp... more Chromaffin cells and sympathetic neurons arise from a common bipotential progenitor which, if exposed to nerve growth factor (NGF), matures into a sympathetic neuron, but if exposed to glucocorticoids (GCs), differentiates into a mature chromaffin cell. Pharmacological evidence indicates that, in adrenal medulla and sympathetic neurons, dopamine (DA) receptors belonging to the D-2 family inhibit catecholamine secretion. The molecular characterization of these receptors, however, is not been yet described. Our data suggest that bipotential cells obtained from newborn rat adrenal medulla express both isoforms of the D-2 receptor, while D-3 receptor and D-4 receptor messenger RNAs (mRNAs) are not present. GC-mediated maturation induces the expression of D-4 receptors, without modification of D-2 isoforms. Sympathetic neurons differentiated in vitro selectively express the D-2short mRNA. Taken together, present results suggest that NGF and GCs play a role in regulating D-2 family receptor expression in neural crest-derived cells.
Exposure of GH-3 cells to epidermal growth factor for 4 consecutive days induced the expression o... more Exposure of GH-3 cells to epidermal growth factor for 4 consecutive days induced the expression of both D-2(415) and D-2(444) dopamine-receptor isoforms. Epidermal growth factor also promoted a remarkable increase in the content of Gi3 protein, which is responsible for receptor-induced activation of potassium channels in GH-3 cells. D-2 receptors in this model apparently activate a specific transducing pathway, leading to opening of potassium channels and inhibition of prolactin release by cAMP-independent mechanisms. This is shown by: 1) the selective D-2 agonist quinpirole, while inactive on vasoactive intestinal peptide-induced prolactin release, strongly inhibited the hormone secretion induced by neurotensin; 2) quinpirole, up to 100 microM, did not inhibit cAMP production evoked by vasoactive intestinal peptide both in intact cells and in broken cell membrane preparations; and 3) quinpirole and other D-2 agonists strongly potentiated Rb+ efflux when measured in a nominally calc...
Inactivation o DA Transporter f I79 2. Wall, SC, Gu, HH, and Rudnick, G. (1995). Biogenic amine f... more Inactivation o DA Transporter f I79 2. Wall, SC, Gu, HH, and Rudnick, G. (1995). Biogenic amine flux mediated by cloned transporters stabiy expressed in cultured cell lines: Amphetamine specificity for inhibition and efflux. Mol. Pharmacol. 47, 544-550. 3. Gu, HH, Ahn, J., Caplan, MJ, ...
Novel structural and functional aspects of the dopamine (DA) D3 receptors (D3R) have been recentl... more Novel structural and functional aspects of the dopamine (DA) D3 receptors (D3R) have been recently described. D3R expressed in dopaminergic neurons have been classically considered to play the role of autoreceptors inhibiting, as the D2R, DA release. However, evidence for D3R-mediated neurotrophic and neuroprotective effects on DA neurons suggests their involvement in preventing pathological alterations leading to neurodegeneration. On the other hand, given its localization and functional role at postsynaptic striatal levels, the D3R may also be involved in the pathogenesis of movement disorders and psychiatric diseases. Functional interactions of D3R with other receptor systems are crucial for the modulation of several physiological events. On this line, the discovery that the D3R can form heteromers with other receptors has opened the possibility of uncover novel molecular mechanisms of brain functions and dysfunctions. This paper summarizes the functional and physical interactions of D3R with other receptors both at pre-synaptic sites, where it is co-expressed with the D2R and nicotinic receptors, and at post-synaptic sites where it interacts with the DA D1 receptors (D1R). The biochemical and functional properties of the D1R-D3R heteromer will be especially discussed. Both D1R and D3R have been in fact implicated in several disorders, including schizophrenia and motor dysfunctions. Therefore, the D1R-D3R heteromer may represent a potential drug target for the treatment of these diseases.
Journal of Cardiovascular Pharmacology - J CARDIOVASC PHARMACOL, 1989
Several studies suggested that dopamine may be one of the inhibitory modulators of aldosterone se... more Several studies suggested that dopamine may be one of the inhibitory modulators of aldosterone secretion. Metoclopramide, a selective antagonist for dopamine D-2 receptors, increases both basal plasma aldosterone levels and the aldosterone response to angiotensin II (Ang II) in rats and humans kept on a high sodium intake, these effects being blocked by dopamine infusion. Dopamine, which has no significant effects on Ang II-induced aldosterone secretion in sodium-replete subjects, inhibits the hormonal response to Ang II infusion in sodium-depleted normal subjects, suggesting that the sodium balance state may be an important factor in the dopaminergic mechanisms controlling aldosterone secretion. The effect of dopamine on the hormone production is mediated by D-2 receptors in the adrenal cortex as shown by in vitro studies with isolated adrenal glomerulosa cells. Clinical studies have shown that dihydroergotoxine, a selective D-2 agonist, suppresses the aldosterone secretion induced by sodium depletion in hypertensive patients, an effect blocked by sulpiride. This mechanism could be of relevant therapeutic interest in its contribution to the natriuretic effects of dopaminergic agonists, which have clinical applications in the treatment of hypertension and congestive heart failure.
In the present study we have investigated the cyclic AMP (cAMP) responses to angiotensin II (AII)... more In the present study we have investigated the cyclic AMP (cAMP) responses to angiotensin II (AII) in isolated rat adrenal glomerulosa cells and in purified membrane preparations. When cells were incubated with 10 nM AII cAMP cellular content increased 2-fold at 5 min and 3-fold at 10 min, then rapidly declined. The effect of AII was dose-dependent with EC50 of 4 nM and was mediated by AII receptors as shown by the pharmacological characterization with AII analogs and AII receptor antagonists. Since AII inhibited cAMP formation in purified adrenal cortical membrane preparations, the stimulatory effect observed in intact cells could be indirect and mediated by other intracellular events.
The ability of the selective D2 dopamine (DA) receptor agonist bromocriptine to inhibit potassium... more The ability of the selective D2 dopamine (DA) receptor agonist bromocriptine to inhibit potassium-induced DA release from striatal slices was measured in rats, which had been unilaterally injected with kainic acid into the left striatum, with the aim of verifying whether the central nervous system contains DA receptors whose stimulation evokes intracellular events which do not involve cyclic AMP. It was found that increasing concentrations of bromocriptine inhibited the potassium-stimulated DA release from rat striatal slices of the kainic acid-treated side with the same potency as in control slices. On the contrary, bromocriptine and the selective D1 agonist SKF 82526 completely lost the ability to inhibit or stimulate, respectively, striatal adenylate cyclase activity from the lesioned side. Our conclusion asserts that inhibition of DA release from rat striatal slices is mediated by stimulation of D2 DA receptors which are fully operative in absence of both DA-stimulated and DA-inhibited adenylate cyclase activity. These data suggest that the intracellular events that follow D2 receptor stimulation in the nigrostriatal nerve terminals may be regulated by second messengers other than cyclic AMP.
We have investigated the distribution of NMDA and neurotrophin receptor systems and their recipro... more We have investigated the distribution of NMDA and neurotrophin receptor systems and their reciprocal interactions in post-synaptic densities (PSD) purified from spinal cord. NMDA receptor subunits, trkA and trkB, but not trkC, were present in spinal cord PSD. The incubation of PSD with BDNF and NGF induced the phosphorylation of NR2A and B subunits. This phosphorylation was counteracted by antibodies directed against the catalytic domain of trkA and trkB receptors and by genistein. These results suggest the existence of a previously unexplored cross-talk between neurotrophins and NMDA receptors in rat spinal cord neurons.
Meningiomas are tumours derived from the arachnoid and pia mater. During embryogenesis, these mem... more Meningiomas are tumours derived from the arachnoid and pia mater. During embryogenesis, these membranes develop from the migrating craniofacial neural crest. We have previously demonstrated that meningiomas have characteristic features of embryonic meninges. Craniofacial neural crest derivatives are affected during normal development and migration by retinoic acid. We speculated, therefore, that meningioma cell migration and invasion would be affected in a similar way. In this study we investigated the mechanisms of invasion and migration in meningiomas and the effects of retinoic acid (RA). We found that low doses of RA inhibit in vitro invasion in meningioma cells, without affecting cell proliferation or viability. The matrix metalloproteinases MMP-2 (72 kDa gelatinase) and MMP-9 (92 kDa gelatinase), which play a key role in invasion in other tumours, are not affected by RA. RA inhibits cell migration on collagen I and fibronectin. A possible mechanism for these effects is provide...
Chromaffin cells and sympathetic neurons arise from a common bipotential progenitor which, if exp... more Chromaffin cells and sympathetic neurons arise from a common bipotential progenitor which, if exposed to nerve growth factor (NGF), matures into a sympathetic neuron, but if exposed to glucocorticoids (GCs), differentiates into a mature chromaffin cell. Pharmacological evidence indicates that, in adrenal medulla and sympathetic neurons, dopamine (DA) receptors belonging to the D-2 family inhibit catecholamine secretion. The molecular characterization of these receptors, however, is not been yet described. Our data suggest that bipotential cells obtained from newborn rat adrenal medulla express both isoforms of the D-2 receptor, while D-3 receptor and D-4 receptor messenger RNAs (mRNAs) are not present. GC-mediated maturation induces the expression of D-4 receptors, without modification of D-2 isoforms. Sympathetic neurons differentiated in vitro selectively express the D-2short mRNA. Taken together, present results suggest that NGF and GCs play a role in regulating D-2 family receptor expression in neural crest-derived cells.
Exposure of GH-3 cells to epidermal growth factor for 4 consecutive days induced the expression o... more Exposure of GH-3 cells to epidermal growth factor for 4 consecutive days induced the expression of both D-2(415) and D-2(444) dopamine-receptor isoforms. Epidermal growth factor also promoted a remarkable increase in the content of Gi3 protein, which is responsible for receptor-induced activation of potassium channels in GH-3 cells. D-2 receptors in this model apparently activate a specific transducing pathway, leading to opening of potassium channels and inhibition of prolactin release by cAMP-independent mechanisms. This is shown by: 1) the selective D-2 agonist quinpirole, while inactive on vasoactive intestinal peptide-induced prolactin release, strongly inhibited the hormone secretion induced by neurotensin; 2) quinpirole, up to 100 microM, did not inhibit cAMP production evoked by vasoactive intestinal peptide both in intact cells and in broken cell membrane preparations; and 3) quinpirole and other D-2 agonists strongly potentiated Rb+ efflux when measured in a nominally calc...
Inactivation o DA Transporter f I79 2. Wall, SC, Gu, HH, and Rudnick, G. (1995). Biogenic amine f... more Inactivation o DA Transporter f I79 2. Wall, SC, Gu, HH, and Rudnick, G. (1995). Biogenic amine flux mediated by cloned transporters stabiy expressed in cultured cell lines: Amphetamine specificity for inhibition and efflux. Mol. Pharmacol. 47, 544-550. 3. Gu, HH, Ahn, J., Caplan, MJ, ...
Novel structural and functional aspects of the dopamine (DA) D3 receptors (D3R) have been recentl... more Novel structural and functional aspects of the dopamine (DA) D3 receptors (D3R) have been recently described. D3R expressed in dopaminergic neurons have been classically considered to play the role of autoreceptors inhibiting, as the D2R, DA release. However, evidence for D3R-mediated neurotrophic and neuroprotective effects on DA neurons suggests their involvement in preventing pathological alterations leading to neurodegeneration. On the other hand, given its localization and functional role at postsynaptic striatal levels, the D3R may also be involved in the pathogenesis of movement disorders and psychiatric diseases. Functional interactions of D3R with other receptor systems are crucial for the modulation of several physiological events. On this line, the discovery that the D3R can form heteromers with other receptors has opened the possibility of uncover novel molecular mechanisms of brain functions and dysfunctions. This paper summarizes the functional and physical interactions of D3R with other receptors both at pre-synaptic sites, where it is co-expressed with the D2R and nicotinic receptors, and at post-synaptic sites where it interacts with the DA D1 receptors (D1R). The biochemical and functional properties of the D1R-D3R heteromer will be especially discussed. Both D1R and D3R have been in fact implicated in several disorders, including schizophrenia and motor dysfunctions. Therefore, the D1R-D3R heteromer may represent a potential drug target for the treatment of these diseases.
Journal of Cardiovascular Pharmacology - J CARDIOVASC PHARMACOL, 1989
Several studies suggested that dopamine may be one of the inhibitory modulators of aldosterone se... more Several studies suggested that dopamine may be one of the inhibitory modulators of aldosterone secretion. Metoclopramide, a selective antagonist for dopamine D-2 receptors, increases both basal plasma aldosterone levels and the aldosterone response to angiotensin II (Ang II) in rats and humans kept on a high sodium intake, these effects being blocked by dopamine infusion. Dopamine, which has no significant effects on Ang II-induced aldosterone secretion in sodium-replete subjects, inhibits the hormonal response to Ang II infusion in sodium-depleted normal subjects, suggesting that the sodium balance state may be an important factor in the dopaminergic mechanisms controlling aldosterone secretion. The effect of dopamine on the hormone production is mediated by D-2 receptors in the adrenal cortex as shown by in vitro studies with isolated adrenal glomerulosa cells. Clinical studies have shown that dihydroergotoxine, a selective D-2 agonist, suppresses the aldosterone secretion induced by sodium depletion in hypertensive patients, an effect blocked by sulpiride. This mechanism could be of relevant therapeutic interest in its contribution to the natriuretic effects of dopaminergic agonists, which have clinical applications in the treatment of hypertension and congestive heart failure.
In the present study we have investigated the cyclic AMP (cAMP) responses to angiotensin II (AII)... more In the present study we have investigated the cyclic AMP (cAMP) responses to angiotensin II (AII) in isolated rat adrenal glomerulosa cells and in purified membrane preparations. When cells were incubated with 10 nM AII cAMP cellular content increased 2-fold at 5 min and 3-fold at 10 min, then rapidly declined. The effect of AII was dose-dependent with EC50 of 4 nM and was mediated by AII receptors as shown by the pharmacological characterization with AII analogs and AII receptor antagonists. Since AII inhibited cAMP formation in purified adrenal cortical membrane preparations, the stimulatory effect observed in intact cells could be indirect and mediated by other intracellular events.
The ability of the selective D2 dopamine (DA) receptor agonist bromocriptine to inhibit potassium... more The ability of the selective D2 dopamine (DA) receptor agonist bromocriptine to inhibit potassium-induced DA release from striatal slices was measured in rats, which had been unilaterally injected with kainic acid into the left striatum, with the aim of verifying whether the central nervous system contains DA receptors whose stimulation evokes intracellular events which do not involve cyclic AMP. It was found that increasing concentrations of bromocriptine inhibited the potassium-stimulated DA release from rat striatal slices of the kainic acid-treated side with the same potency as in control slices. On the contrary, bromocriptine and the selective D1 agonist SKF 82526 completely lost the ability to inhibit or stimulate, respectively, striatal adenylate cyclase activity from the lesioned side. Our conclusion asserts that inhibition of DA release from rat striatal slices is mediated by stimulation of D2 DA receptors which are fully operative in absence of both DA-stimulated and DA-inhibited adenylate cyclase activity. These data suggest that the intracellular events that follow D2 receptor stimulation in the nigrostriatal nerve terminals may be regulated by second messengers other than cyclic AMP.
We have investigated the distribution of NMDA and neurotrophin receptor systems and their recipro... more We have investigated the distribution of NMDA and neurotrophin receptor systems and their reciprocal interactions in post-synaptic densities (PSD) purified from spinal cord. NMDA receptor subunits, trkA and trkB, but not trkC, were present in spinal cord PSD. The incubation of PSD with BDNF and NGF induced the phosphorylation of NR2A and B subunits. This phosphorylation was counteracted by antibodies directed against the catalytic domain of trkA and trkB receptors and by genistein. These results suggest the existence of a previously unexplored cross-talk between neurotrophins and NMDA receptors in rat spinal cord neurons.
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