12 results on '"Rodríguez, Silvia Susana"'
Search Results
2. Constitutive activity of the dopamine (D 5 ) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces Ca V 3.2 and Ca V 3.3 currents
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Mustafá, Emilio Román, primary, McCarthy, Clara Inés, additional, Portales, Andrea Estefanía, additional, Cordisco Gonzalez, Santiago, additional, Rodríguez, Silvia Susana, additional, and Raingo, Jesica, additional
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- 2023
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3. Functional alterations of two novel MC4R mutations found in Argentinian pediatric patients with early onset obesity
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Fernández, Estefanía, primary, McCarthy, Clara Inés, additional, Cerviño, Ramiro Hector, additional, Rodríguez, Silvia Susana, additional, Yaneff, Agustín, additional, Hernández, Julieta, additional, Garrido, Verónica, additional, Di Rocco, Florencia, additional, and Raingo, Jesica, additional
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- 2023
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4. Chlorpromazine, an Inverse Agonist of D1R-Like, Differentially Targets Voltage-Gated Calcium Channel (CaV) Subtypes in mPFC Neurons.
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McCarthy, Clara Inés, Mustafá, Emilio Román, Cornejo, María Paula, Yaneff, Agustín, Rodríguez, Silvia Susana, Perello, Mario, and Raingo, Jesica
- Abstract
The dopamine receptor type 1 (D1R) and the dopamine receptor type 5 (D5R), which are often grouped as D1R-like due to their sequence and signaling similarities, exhibit high levels of constitutive activity. The molecular basis for this agonist-independent activation has been well characterized through biochemical and mutagenesis in vitro studies. In this regard, it was reported that many antipsychotic drugs act as inverse agonists of D1R-like constitutive activity. On the other hand, D1R is highly expressed in the medial prefrontal cortex (mPFC), a brain area with important functions such as working memory. Here, we studied the impact of D1R-like constitutive activity and chlorpromazine (CPZ), an antipsychotic drug and D1R-like inverse agonist, on various neuronal Ca
V conductances, and we explored its effect on calcium-dependent neuronal functions in the mouse medial mPFC. Using ex vivo brain slices containing the mPFC and transfected HEK293T cells, we found that CPZ reduces CaV 2.2 currents by occluding D1R-like constitutive activity, in agreement with a mechanism previously reported by our lab, whereas CPZ directly inhibits CaV 1 currents in a D1R-like activity independent manner. In contrast, CPZ and D1R constitutive activity did not affect CaV 2.1, CaV 2.3, or CaV 3 currents. Finally, we found that CPZ reduces excitatory postsynaptic responses in mPFC neurons. Our results contribute to understanding CPZ molecular targets in neurons and describe a novel physiological consequence of CPZ non-canonical action as a D1R-like inverse agonist in the mouse brain. [ABSTRACT FROM AUTHOR]- Published
- 2023
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5. Constitutive activity of the dopamine (D5) receptor, highly expressed in CA1 hippocampal neurons, selectively reduces CaV3.2 and CaV3.3 currents.
- Author
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Mustafá, Emilio Román, McCarthy, Clara Inés, Portales, Andrea Estefanía, Cordisco Gonzalez, Santiago, Rodríguez, Silvia Susana, and Raingo, Jesica
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DOPAMINE receptors ,DOPAMINERGIC neurons ,PYRAMIDAL neurons ,G protein coupled receptors ,NEURONS ,HIPPOCAMPUS (Brain) ,DOPAMINE - Abstract
Background and Purpose: CaV3.1‐3 currents differentially contribute to neuronal firing patterns. CaV3 are regulated by G protein‐coupled receptors (GPCRs) activity, but information about CaV3 as targets of the constitutive activity of GPCRs is scarce. We investigate the impact of D5 recpetor constitutive activity, a GPCR with high levels of basal activity, on CaV3 functionality. D5 recpetor and CaV3 are expressed in the hippocampus and have been independently linked to pathophysiological states associated with epilepsy. Experimental Approach: Our study models were HEK293T cells heterologously expressing D1 or D5 receptor and CaV3.1‐3, and mouse brain slices containing the hippocampus. We used chlorpromazine (D1/D5 inverse agonist) and a D5 receptor mutant lacking constitutive activity as experimental tools. We measured CaV3 currents and excitability parameters using the patch‐clamp technique. We completed our study with computational modelling and imaging technique. Key Results: We found a higher sensitivity to TTA‐P2 (CaV3 blocker) in CA1 pyramidal neurons obtained from chlorpromazine‐treated animals compared with vehicle‐treated animals. We found that CaV3.2 and CaV3.3—but not CaV3.1—are targets of D5 receptor constitutive activity in HEK293T cells. Finally, we found an increased firing rate in CA1 pyramidal neurons from chlorpromazine‐treated animals in comparison with vehicle‐treated animals. Similar changes in firing rate were observed on a neuronal model with controlled CaV3 currents levels. Conclusions and Implications: Native hippocampal CaV3 and recombinant CaV3.2‐3 are sensitive to D5 receptor constitutive activity. Manipulation of D5 receptor constitutive activity could be a valuable strategy to control neuronal excitability, especially in exacerbated conditions such as epilepsy. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons
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McCarthy, Clara Inés, primary, Chou-Freed, Cambria, additional, Rodríguez, Silvia Susana, additional, Yaneff, Agustín, additional, Davio, Carlos, additional, and Raingo, Jesica, additional
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- 2020
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7. Growth hormone secretagogue receptor constitutive activity impairs voltage-gated calcium channel-dependent inhibitory neurotransmission in hippocampal neurons
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Martínez Damonte, Valentina, Rodríguez, Silvia Susana, and Raingo, Jesica
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SYNAPSE ,CIENCIAS MÉDICAS Y DE LA SALUD ,digestive, oral, and skin physiology ,Ciencias de la Salud ,PRIMARY CULTURES ,ELECTROPHYSIOLOGY ,INHIBITORY POSTSYNAPTIC CURRENT ,Otras Ciencias de la Salud ,purl.org/becyt/ford/3.3 [https] ,GABA ,GPCR ,BRAIN SLICES ,purl.org/becyt/ford/3 [https] ,GHRELIN - Abstract
Key points: Presynaptic CaV2 voltage-gated calcium channels link action potentials arriving at the presynaptic terminal to neurotransmitter release. Hence, their regulation is essential to fine tune brain circuitry. CaV2 channels are highly sensitive to G protein-coupled receptor (GPCR) modulation. Our previous data indicated that growth hormone secretagogue receptor (GHSR) constitutive activity impairs CaV2 channels by decreasing their surface density. We present compelling support for the impact of CaV2.2 channel inhibition by agonist-independent GHSR activity exclusively on GABA release in hippocampal cultures. We found that this selectivity arises from a high reliance of GABA release on CaV2.2 rather than on CaV2.1 channels. Our data provide new information on the effects of the ghrelin–GHSR system on synaptic transmission, suggesting a putative physiological role of the constitutive signalling of a GPCR that is expressed at high levels in brain areas with restricted access to its natural agonist. Abstract: Growth hormone secretagogue receptor (GHSR) displays high constitutive activity, independent of its endogenous ligand, ghrelin. Unlike ghrelin-induced GHSR activity, the physiological role of GHSR constitutive activity and the mechanisms that underlie GHSR neuronal modulation remain elusive. We previously demonstrated that GHSR constitutive activity modulates presynaptic CaV2 voltage-gated calcium channels. Here we postulate that GHSR constitutive activity-mediated modulation of CaV2 channels could be relevant in the hippocampus since this brain area has high GHSR expression but restricted access to ghrelin. We performed whole-cell patch-clamp in hippocampal primary cultures from E16- to E18-day-old C57BL6 wild-type and GHSR-deficient mice after manipulating GHSR expression with lentiviral transduction. We found that GHSR constitutive activity impairs CaV2.1 and CaV2.2 native calcium currents and that CaV2.2 basal impairment leads to a decrease in GABA but not glutamate release. We postulated that this selective effect is related to a higher CaV2.2 over CaV2.1 contribution to GABA release (∼40% for CaV2.2 in wild-type vs. ∼20% in wild-type GHSR-overexpressing cultures). This effect of GHSR constitutive activity is conserved in hippocampal brain slices, where GHSR constitutive activity reduces local GABAergic transmission of the granule cell layer (intra-granule cell inhibitory postsynaptic current (IPSC) size ∼−67 pA in wild-type vs. ∼−100 pA in GHSR-deficient mice), whereas the glutamatergic output from the dentate gyrus to CA3 remains unchanged. In summary, we found that GHSR constitutive activity impairs IPSCs both in hippocampal primary cultures and in brain slices through a CaV2-dependent mechanism without affecting glutamatergic transmission. Fil: Martínez Damonte, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Rodríguez, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Raingo, Jesica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
- Published
- 2018
8. Constitutive activity of the Ghrelin receptor reduces surface expression of voltage-gated Ca2+ channels in a CaVβ-dependent manner
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Mustafá, Emilio Román, López Soto, Eduardo Javier, Martínez Damonte, Valentina, Rodríguez, Silvia Susana, Lipscombe, Diane, and Raingo, Jesica
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Medicina Básica ,CIENCIAS MÉDICAS Y DE LA SALUD ,CaVβ ,GPCR ,Biología ,Voltage-gated calcium (Ca2+) channels ,Inmunología ,cardiovascular system ,purl.org/becyt/ford/3 [https] ,purl.org/becyt/ford/3.1 [https] ,VOLTAGE-GATED CALCIUM (CA2+) CHANNELS ,CAV&Beta - Abstract
Voltage-gated Ca2+ (CaV) channels couple membrane depolarization to Ca2+ influx, triggering a range ofCa2+-dependent cellular processes. CaV channels are, therefore, crucial in shaping neuronal activity and function, depending on their individual temporal and spatial properties. Furthermore, many neurotransmitters and drugs that act through G protein coupled receptors (GPCRs), modulate neuronal activity by altering the expression, trafficking, or function of CaV channels. GPCRdependent mechanisms that downregulate CaV channel expression levels are observed in many neurons but are, by comparison, less studied. Herewe showthat the growth hormone secretagogue receptor type 1a (GHSR), a GPCR, can inhibit the forwarding trafficking of severalCaV subtypes, even in the absence of agonist. This constitutive form ofGPCRinhibition of CaV channels depends on the presence of a CaVβ subunit. CaVβ subunits displace CaVα1 subunits from the endoplasmic reticulum. The actions of GHSR on CaV channels trafficking suggest a role for this signaling pathway in brain areas that control food intake, reward, and learning and memory., Instituto Multidisciplinario de Biología Celular
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- 2017
9. Growth hormone secretagogue receptor constitutive activity impairs voltage‐gated calcium channel‐dependent inhibitory neurotransmission in hippocampal neurons
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Martínez Damonte, Valentina, primary, Rodríguez, Silvia Susana, additional, and Raingo, Jesica, additional
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- 2018
- Full Text
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10. Gene therapy for the treatment of pituitary tumors
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Rodríguez, Silvia Susana, Castro, María Graciela, Brown, Oscar Alfredo, Goya, Rodolfo Gustavo, and Cónsole-Avegliano, Gloria Miriam
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Viral vectors ,Gene therapy ,Proapoptotic genes ,Suicide gene therapy ,Ciencias Médicas ,Neurosurgery ,Pituitary tumors ,Combined therapy ,IGF-I gene therapy - Abstract
Pituitary adenomas constitute the most frequent neuroendocrine pathology in humans. Current therapies include surgery, radiotherapy and pharmacological approaches. Although useful, none of them offers a permanent cure. Current research efforts to implement gene therapy in pituitary tumors include the treatment of experimental adenomas with adenoviral vector-mediated transfer of the suicide gene for thymidine kinase, which converts the prodrug ganciclovir into a toxic metabolite. In some cases, the suicide transgene has been placed under the control of pituitary cell-type specific promoters. Also, regulatable adenoviral vector systems are being assessed in gene therapy approaches for experimental pituitary tumors. Although the efficiency and safety of current viral vectors must be optimized before clinical use, they remain as highly promising therapeutic tools., Instituto de Investigaciones Bioquímicas de La Plata, Comisión de Investigaciones Científicas de la provincia de Buenos Aires
- Published
- 2009
11. The thymus-neuroendocrine axis: physiology, molecular biology, and therapeutic potential of the thymic peptide thymulin
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Reggiani, Paula Cecilia, Morel, Gustavo Ramón, Console de Avegliano, Gloria Miriam, Barbeito, Claudio Gustavo, Rodríguez, Silvia Susana, Brown, Oscar Alfredo, Bellini, María José, Pleau, Jean-Marie, Dardenne, Mireille, and Goya, Rodolfo Gustavo
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Thymulin ,Gene therapy ,Ovarian dysgenesis ,Artificial gene ,Ciencias Médicas ,Antiinflammatory ,Hypophysiotropic activity ,Neuroendocrine control - Abstract
Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. It consists of a nonapeptide component coupled to the ion zinc, which confers biological activity to the molecule. After its discovery in the early 1970s, thymulin was characterized as a thymic hormone involved in several aspects of intrathymic and extrathymic T cell differentiation. Subsequently, it was demonstrated that thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to thymulin as a hypophysotropic peptide. In recent years, interest has arisen in the potential use of thymulin as a therapeutic agent. Thymulin was shown to possess anti-inflammatory and analgesic properties in the brain. Furthermore, an adenoviral vector harboring a synthetic gene for thymulin, stereotaxically injected in the rat brain, achieved a much longer expression than the adenovirally mediated expression in the brain of other genes, thus suggesting that an anti-inflammatory activity of thymulin prevents the immune system from destroying virus-transduced brain cells. Other studies suggest that thymulin gene therapy may also be a suitable therapeutic strategy to prevent some of the endocrine and metabolic alterations that typically appear in thymus-deficient animal models. The present article briefly reviews the literature on the physiology, molecular biology, and therapeutic potential of thymulin., Instituto de Investigaciones Bioquímicas de La Plata, Facultad de Ciencias Veterinarias, Comisión de Investigaciones Científicas de la provincia de Buenos Aires
- Published
- 2009
12. Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons.
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McCarthy, Clara Inés, Cambria Chou-Freed, Rodríguez, Silvia Susana, Yaneff, Agustín, Davio, Carlos, and Raingo, Jesica
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PYRAMIDAL neurons , *DOPAMINE receptors , *NEURONS , *CALCIUM channels , *PREFRONTAL cortex , *SHORT-term memory - Abstract
Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events triggered by changes in D1R expression remain unknown. A previous report demonstrated that interaction between voltage-gated calcium channel type 2.2 (CaV2.2) and D1R stimulates CaV2.2 postsynaptic surface location in medial PFC pyramidal neurons. Here, we show that in addition to the occurrence of the physical receptor-channel interaction, constitutive D1R activity mediates up-regulation of functional CaV2.2 surface density. We performed patch-clamp experiments on transfected HEK293T cells and wild-type C57BL/6 mouse brain slices, as well as imaging experiments and cAMP measurements. We found that D1R coexpression led to ~60% increase in CaV2.2 currents in HEK293T cells. This effect was occluded by preincubation with a D1/D5R inverse agonist, chlorpromazine, and by replacing D1R with a D1R mutant lacking constitutive activity. Moreover, D1R-induced increase in CaV2.2 currents required basally active Gs protein, as well as D1R-CaV2.2 interaction. In mice, intraperitoneal administration of chlorpromazine reduced native CaV currents' sensitivity to γ-conotoxin-GVIA and their size by ~49% in layer V/VI pyramidal neurons from medial PFC, indicating a selective effect on CaV2.2. Additionally, we found that reducing D1/D5R constitutive activity correlates with a decrease in the agonist-induced D1/D5R inhibitory effect on native CaV currents. Our results could be interpreted as a stimulatory effect of D1R constitutive activity on the number of CaV2.2 channels available for dopamine-mediated modulation. Our results contribute to the understanding of the physiological role of D1R constitutive activity and may explain the noncanonical postsynaptic distribution of functional CaV2.2 in PFC neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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