Biased GPCR signaling by the native parathyroid hormone–related protein 1 to 141 relative to its N-terminal fragment 1 to 36

International audienceThe parathyroid hormone (PTH)–related protein (PTHrP) is indispensable for the development of mammary glands, placental calcium ion transport, tooth eruption, bone formation and bone remodeling, and causes hypercalcemia in patients with malignancy. Although mature forms of PTHrP in the body consist of splice variants of 139, 141, and 173 amino acids, our current understanding on how endogenous PTHrP transduces signals through its cognate G-protein coupled receptor (GPCR), the PTH type 1 receptor (PTHR), is largely derived from studies done with its N-terminal fragment, PTHrP1-36. Here, we demonstrate using various fluorescence imaging approaches at the single cell level to measure kinetics of (i) receptor activation, (ii) receptor signaling via Gs and Gq, and (iii) receptor internalization and recycling that the native PTHrP1-141 displays biased agonist signaling properties that are not mimicked by PTHrP1-36. Although PTHrP1–36 induces transient cAMP production, acute intracellular Ca2+ (iCa2+) release and β-arrestin recruitment mediated by ligand–PTHR interactions at the plasma membrane, PTHrP1-141 triggers sustained cAMP signaling from the plasma membrane and fails to stimulate iCa2+ release and recruit β-arrestin. Furthermore, we show that the molecular basis for biased signaling differences between PTHrP1-36 and properties of native PTHrP1-141 are caused by the stabilization of a singular PTHR conformation and PTHrP1-141 sensitivity to heparin, a sulfated glycosaminoglycan. Taken together, our results contribute to a better understanding of the biased signaling process of a native protein hormone acting in conjunction with a GPCR

Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release

G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT signal-transduction pathway inhibiting stress-mediated cytochrome release and caspase activation. These findings coupled with our observation that mitochondrial MT overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, automitocrine, analogous to autocrine when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand-receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology

Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release

International audienc

Pesquisa clínica e experimental no Brasil oitocentista: circulação e controle do conhecimento em helmintologia médica Clinical and experimental research in nineteenth-century Brazil: the circulation and control of knowledge in medical helminthology

As contribuições de médicos brasileiros ao conhecimento sobre doenças causadas por vermes parasitas, na segunda metade do século XIX, produziram efeitos distintos em três comunidades epistêmicas: a anatomoclínica brasileira; a geografia médica francesa; e a emergente parasitologia médica. Admitindo a heterogeneidade dos regimes de legitimação dos fatos científicos e das práticas epistemológicas, descreve-se cartografia específica do conhecimento médico da época, revelando as linhas de força dos três campos disciplinares. O foco na circulação, no controle e na validação do conhecimento médico revela controvérsias e complicadas negociações entre distintas comunidades epistêmicas.<br>The contributions of Brazilian physicians to knowledge of diseases caused by parasitic worms, during the second half of the nineteenth century, had distinct effects on three epistemic communities: Brazilian clinical anatomy, French medical geography, and the emerging field of medical parasitology. Accepting the heterogeneity of both the systems for legitimizing scientific facts and the epistemological practices observed by each discipline, the text provides a specific cartography of the period's medical knowledge, revealing the lines of force shaping the three disciplinary fields. The focus on the circulation, control and validation of medical knowledge reveals strong controversies and complicated negotiations between different epistemic communities

As investigações dos fenômenos psíquicos/espirituais no século XIX: sonambulismo e espiritualismo, 1811-1860

Resumo No início do século XIX, investigações sobre a natureza de fenômenos psíquicos/espirituais como transes e supostas aquisições de informações indisponíveis aos canais sensoriais normais geraram grande debate no meio científico. Este artigo discute as principais explicações oferecidas pelos pesquisadores dos fenômenos psíquicos entre 1811 e 1860, concentrando-se nos dois movimentos principais no período: sonambulismo magnético e espiritualismo moderno. As investigações desses fenômenos geraram diversas teorias, sem que se chegasse a consenso, mas trouxeram implicações para a compreensão da mente e de seus transtornos, notadamente na área do inconsciente e da dissociação, constituindo-se como parte importante da história da psicologia e da psiquiatria