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Start Over Author "Franco, Rafael" Journal british journal of pharmacology
10 results on '"Franco, Rafael"'

1. Gonadal hormone‐independent sex differences in GABA A receptor activation in rat embryonic hypothalamic neurons

Author

Luis G. Aguayo, Carlos Wilson, Lucas Ezequiel Cabrera Zapata, Franco Rafael Mir, and María Julia Cambiasso

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Hypothalamus, Biology, SEX DIFFERENCES, CALCIUM, GABAAR COMPOSITION, GABA, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Animals, Receptor, Neurons, Pharmacology, Sex Characteristics, GABAA receptor, purl.org/becyt/ford/3.1 [https], Receptors, GABA-A, ELECTROPHYSIOLOGY, Research Papers, Embryonic stem cell, Rats, 030104 developmental biology, Endocrinology, nervous system, Female, purl.org/becyt/ford/3 [https], Gonadal Hormones, 030217 neurology & neurosurgery, Gonadal hormones
Abstract

Background and Purpose: GABAA receptor functions are dependent on subunit composition, and, through their activation, GABA can exert trophic actions in immature neurons. Although several sex differences in GABA-mediated responses are known to be dependent on gonadal hormones, few studies have dealt with sex differences detected before the critical period of brain masculinisation. In this study, we assessed GABAA receptor functionality in sexually segregated neurons before brain hormonal masculinisation. Experimental Approach: Ventromedial hypothalamic neurons were obtained from embryonic day 16 rat brains and grown in vitro for 2 days. Calcium imaging and electrophysiology recordings were carried out to assess GABAA receptor functional parameters. Key Results: GABAA receptor activation elicited calcium entry in immature hypothalamic neurons mainly through L-type voltage-dependent calcium channels. Nifedipine blocked calcium entry more efficiently in male than in female neurons. There were more male than female neurons responding to GABA, and they needed more time to return to resting levels. Pharmacological characterisation revealed that propofol enhanced GABAA-mediated currents and blunted GABA-mediated calcium entry more efficiently in female neurons than in males. Testosterone treatment did not erase such sex differences. These data suggest sex differences in the expression of GABAA receptor subtypes. Conclusion and Implications: GABA-mediated responses are sexually dimorphic even in the absence of gonadal hormone influence, suggesting genetically biased differences. These results highlight the importance of GABAA receptors in hypothalamic neurons even before hormonal masculinisation of the brain. Fil: Mir, Franco Rafael. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de La Rioja; Argentina Fil: Wilson Rodriguez, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina Fil: Cabrera Zapata, Lucas Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina Fil: Aguayo, Luis G.. Universidad de Concepción; Chile Fil: Cambiasso, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Cordoba. Facultad de Odontologia. Departamento de Biologia Bucal; Argentina

Published
2020

2. Carnitine palmitoyltransferase 1C negatively regulates the endocannabinoid hydrolase ABHD6 in mice, depending on nutritional status

Author

Miralpeix, Cristina, primary, Reguera, Ana Cristina, additional, Fosch, Anna, additional, Casas, Maria, additional, Lillo, Jaume, additional, Navarro, Gemma, additional, Franco, Rafael, additional, Casas, Josefina, additional, Alexander, Stephen P.H., additional, Casals, Núria, additional, and Rodríguez‐Rodríguez, Rosalía, additional

Published
2021
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9. Progress on the development of Class A GPCR‐biased ligands.

Author

Morales, Paula, Scharf, Magdalena M., Bermudez, Marcel, Egyed, Attila, Franco, Rafael, Hansen, Olivia K., Jagerovic, Nadine, Jakubík, Jan, Keserű, György M., Kiss, Dóra Judit, Kozielewicz, Pawel, Larsen, Olav, Majellaro, Maria, Mallo‐Abreu, Ana, Navarro, Gemma, Prieto‐Díaz, Rubén, Rosenkilde, Mette M., Sotelo, Eddy, Stark, Holger, and Werner, Tobias

Subjects
*DRUG discovery, *LIGANDS (Biochemistry), *CELL communication, *DRUG target, *CLINICAL medicine, *G protein coupled receptors
Abstract

Class A G protein‐coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR‐biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Allosterism in the adenosine A2A and cannabinoid CB2 heteromer.

Author

Llinas del Torrent, Claudia, Raïch, Iu, Gonzalez, Angel, Lillo, Jaume, Casajuana‐Martin, Nil, Franco, Rafael, Pardo, Leonardo, and Navarro, Gemma

Subjects
*G protein coupled receptors, *ALLOSTERIC regulation, *AMINO acid sequence, *G proteins, *PEPTIDOMIMETICS, *ADENOSINES
Abstract

Background and Purpose Experimental Approach Key Results Conclusions and Implications Allosterism is a regulatory mechanism for GPCRs that can be attained by ligand‐binding or protein–protein interactions with another GPCR. We have studied the influence of the dimer interface on the allosteric properties of the A2A receptor and CB2 receptor heteromer.We have evaluated cAMP production, phosphorylation of signal‐regulated kinases (pERK1/2), label‐free dynamic mass redistribution, β‐arrestin 2 recruitment and bimolecular fluorescence complementation assays in the absence and presence of synthetic peptides that disrupt the formation of the heteromer. Molecular dynamic simulations provided converging evidence that the heteromeric interface influences the allosteric properties of the A2AR–CB2R heteromer.Apo A2AR blocks agonist‐induced signalling of CB2R. The disruptive peptides, with the amino acid sequence of transmembrane (TM) 6 of A2AR or CB2R, facilitate CB2R activation, suggesting that A2AR allosterically prevents the outward movement of TM 6 of CB2R for G protein binding. Significantly, binding of the selective antagonist SCH 58261 to A2AR also facilitated agonist‐induced activation of CB2R.It is proposed that the A2AR–CB2R heteromer contains distinct dimerization interfaces that govern its functional properties. The molecular interface between protomers of the A2AR–CB2R heteromer interconverted from TM 6 for apo or agonist‐bound A2AR, blocking CB2R activation, to mainly the TM 1/7 interface for antagonist‐bound A2AR, facilitating the independent opening of intracellular cavities for G protein binding. These novel results shed light on a different type of allosteric mechanism and extend the repertoire of GPCR heteromer signalling. [ABSTRACT FROM AUTHOR]

Published
2024
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