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1.
Proc Natl Acad Sci U S A ; 110(6): 2383-8, 2013 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-23345429

RESUMO

Human skin is constantly exposed to solar ultraviolet radiation (UVR), the most prevalent environmental carcinogen. Humans have the unique ability among mammals to respond to UVR by increasing their skin pigmentation, a protective process driven by melanin synthesis in epidermal melanocytes. The molecular mechanisms used by melanocytes to detect and respond to long-wavelength UVR (UVA) are not well understood. We recently identified a UVA phototransduction pathway in melanocytes that is mediated by G protein-coupled receptors and leads to rapid calcium mobilization. Here we report that in human epidermal melanocytes physiological doses of UVR activate a retinal-dependent current mediated by transient receptor potential A1 (TRPA1) ion channels. The TRPA1 photocurrent is UVA-specific and requires G protein and phospholipase C signaling, thus contributing to UVA-induced calcium responses to mediate downstream cellular effects and providing evidence for TRPA1 function in mammalian phototransduction. Remarkably, TRPA1 activation is required for the UVR-induced and retinal-dependent early increase in cellular melanin. Our results show that TRPA1 is essential for a unique extraocular phototransduction pathway in human melanocytes that is activated by physiological doses of UVR and results in early melanin synthesis.


Assuntos
Canais de Cálcio/metabolismo , Canais de Cálcio/efeitos da radiação , Transdução de Sinal Luminoso/fisiologia , Transdução de Sinal Luminoso/efeitos da radiação , Melanócitos/metabolismo , Melanócitos/efeitos da radiação , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/efeitos da radiação , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Potencial de Receptor Transitório/efeitos da radiação , Animais , Células CHO , Canais de Cálcio/genética , Sinalização do Cálcio/efeitos da radiação , Células Cultivadas , Cricetinae , Cricetulus , Proteínas de Ligação ao GTP/metabolismo , Humanos , Melaninas/biossíntese , Modelos Biológicos , Proteínas do Tecido Nervoso/genética , Técnicas de Patch-Clamp , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/genética , Raios Ultravioleta
2.
J Neuroendocrinol ; 32(1): e12801, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605642

RESUMO

Sex differences among neurones in the ventrolateral region of the ventromedial hypothalamic nucleus (VMHvl) allow for the display of a diversity of sex-typical behaviours and physiological responses, ranging from mating behaviour to metabolism. Here, we review recent studies that interrogate the relationship between sex-typical responses and changes in cellular phenotypes. We discuss technologies that increase the resolution of molecular profiling or targeting of cell populations, including single-cell transcriptional profiling and conditional viral genetic approaches to manipulate neurone survival or activity. Overall, emerging studies indicate that sex-typical functions of the VMH may be mediated by phenotypically distinct and sexually differentiated neurone populations within the VMHvl. Future studies in this and other brain regions could exploit cell-type-specific tools to reveal the cell populations and molecular mediators that modulate sex-typical responses. Furthermore, cell-type-specific analyses of the effects of sexually differentiating factors, including sex hormones, can test the hypothesis that distinct cell types within a single brain region vary with respect to sexual differentiation.


Assuntos
Neurônios/metabolismo , Caracteres Sexuais , Diferenciação Sexual/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Feminino , Humanos , Masculino , Comportamento Sexual Animal/fisiologia
3.
Nat Metab ; 2(4): 351-363, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32377634

RESUMO

Estrogen receptor a (ERa) signaling in the ventromedial hypothalamus (VMH) contributes to energy homeostasis by modulating physical activity and thermogenesis. However, the precise neuronal populations involved remain undefined. Here, we describe six neuronal populations in the mouse VMH by using single-cell RNA transcriptomics and in situ hybridization. ERa is enriched in populations showing sex biased expression of reprimo (Rprm), tachykinin 1 (Tac1), and prodynorphin (Pdyn). Female biased expression of Tac1 and Rprm is patterned by ERa-dependent repression during male development, whereas male biased expression of Pdyn is maintained by circulating testicular hormone in adulthood. Chemogenetic activation of ERa positive VMH neurons stimulates heat generation and movement in both sexes. However, silencing Rprm gene function increases core temperature selectively in females and ectopic Rprm expression in males is associated with reduced core temperature. Together these findings reveal a role for Rprm in temperature regulation and ERa in the masculinization of neuron populations that underlie energy expenditure.


Assuntos
Metabolismo Energético , Receptor alfa de Estrogênio/metabolismo , Hipotálamo/metabolismo , Caracteres Sexuais , Animais , Feminino , Corantes Fluorescentes/química , Marcadores Genéticos , Hipotálamo/citologia , Masculino , Camundongos , Neurônios/metabolismo
4.
Neuroscience ; 395: 89-100, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30447391

RESUMO

Cognitive impairment (CI), a debilitating and pervasive feature of multiple sclerosis (MS), is correlated with hippocampal atrophy. Findings from postmortem MS hippocampi indicate that expression of genes involved in both excitatory and inhibitory neurotransmission are altered in MS, and although deficits in excitatory neurotransmission have been reported in the MS model experimental autoimmune encephalomyelitis (EAE), the functional consequence of altered inhibitory neurotransmission remains poorly understood. In this study, we used electrophysiological and biochemical techniques to examine inhibitory neurotransmission in the CA1 region of the hippocampus in EAE. We find that tonic, GABAergic inhibition is enhanced in CA1 pyramidal cells from EAE mice. Although plasma membrane expression of the GABA transporter GAT-3 was decreased in the EAE hippocampus, an increased surface expression of α5 subunit-containing GABAA receptors appears to be primarily responsible for the increase in tonic inhibition during EAE. Enhanced tonic inhibition during EAE was associated with decreased CA1 pyramidal cell excitability and inhibition of α5 subunit-containing GABAA receptors with the negative allosteric modulator L-655,708 enhanced pyramidal cell excitability in EAE mice. Together, our results suggest that altered GABAergic neurotransmission may underlie deficits in hippocampus-dependent cognitive function in EAE and MS.


Assuntos
Região CA1 Hipocampal/fisiopatologia , Encefalomielite Autoimune Experimental/fisiopatologia , Inibição Neural/fisiologia , Células Piramidais/fisiologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Camundongos , Inibição Neural/efeitos dos fármacos , Técnicas de Patch-Clamp , Células Piramidais/efeitos dos fármacos , Piridazinas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
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