RESUMEN
The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain nuclei playing a crucial role in the regulation of energy balance controlling the homeostasis of the organism. It displays both agonist-evoked and constitutive activity, and moreover, it can couple to different G proteins. Most of the research on MC4R has been focused on agonist-induced activity, while the molecular and cellular basis of MC4R constitutive activity remains scarcely studied. We have previously shown that neuronal N-type voltage-gated calcium channels (CaV2.2) are inhibited by MC4R agonist-dependent activation, while the CaV subtypes that carry L- and P/Q-type current are not. Here, we tested the hypothesis that MC4R constitutive activity can affect CaV, with focus on the channel subtypes that can control transcriptional activity coupled to depolarization (L-type, CaV1.2/1.3) and neurotransmitter release (N- and P/Q-type, CaV2.2 and CaV2.1). We found that MC4R constitutive activity inhibits specifically CaV1.2/1.3 and CaV2.1 subtypes of CaV. We also explored the signaling pathways mediating this inhibition, and thus propose that agonist-dependent and basal MC4R activation modes signal differentially through Gs and Gi/o pathways to impact on different CaV subtypes. In addition, we found that chronic incubation with MC4R endogenous inverse agonist, agouti and agouti-related peptide (AgRP), occludes CaV inhibition in a cell line and in amygdaloid complex cultured neurons as well. Thus, we define new mechanisms of control of the main mediators of depolarization-induced calcium entry into neurons by a GPCR that displays constitutive activity.
Asunto(s)
Canales de Calcio Tipo L/fisiología , Neuronas/fisiología , Receptor de Melanocortina Tipo 4/fisiología , Proteína Relacionada con Agouti/administración & dosificación , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiología , Animales , Femenino , Proteínas de Unión al GTP/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptor de Melanocortina Tipo 4/agonistas , Transducción de SeñalRESUMEN
Los autores reprodujeron experimentalmente el proceso de eliminación transepidérmica en piel de cobayo. La técnica utilizada fue la inyección de carbón animal a nivel dérmico, en piel pilosa y glabra. Las biopsias realizadas a partir del cuarto día después del procedimiento mostraron distintos patrones de eliminación transepidérmica. En piel pilosa se observó una imagen similar a foliculitis perforante mientras que en piel glabra se reprodujo el fenómeno de la colagenosis perforante reactiva. La microscopia electrónica mostró desmosomas intactos en las zonas de extrusión y macrófagos activados con partículas de carbón intracelulares
Asunto(s)
Humanos , Animales , Masculino , Femenino , Cobayas , Epidermis/metabolismo , Enfermedades de la Piel/patología , Biopsia , Carbón Orgánico/administración & dosificación , Ensayo Clínico , Inyecciones Intradérmicas , Microscopía ElectrónicaRESUMEN
A hemofiltracao foi estudada em 7 caes, durante circulacao extracorporea. O hemodialisador tipo bobina (Travenol CD-1000) foi empregado, em substituicao ao hemofiltro padrao, variando-se a pressao transmembrana e o fluxo de perfusao no dialisador. O maior volume/minuto de ultrafiltrado (36,6 ml min) foi obtido com o uso de pressao negativa, aplicada em circuito especial no hemodialisador (com 650 ml/min de fluxo de perfusao). Menos importantes para a eficiencia da ultrafiltracao foram as variacoes da pressao positiva no hemodialisador