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HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model.
Sztukowski, Keira; Nip, Kaila; Ostwald, Paige N; Sathler, Matheus F; Sun, Julianna L; Shou, Jiayi; Jorgensen, Emily T; Brown, Travis E; Elder, John H; Miller, Craig; Hofmann, Franz; VandeWoude, Sue; Kim, Seonil.
Afiliação
  • Sztukowski K; College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
  • Nip K; Cellular and Molecular Biology Graduate Program, Colorado State University, Fort Collins, Colorado, United States of America.
  • Ostwald PN; Cellular and Molecular Biology Graduate Program, Colorado State University, Fort Collins, Colorado, United States of America.
  • Sathler MF; Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
  • Sun JL; Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
  • Shou J; Molecular, Cellular and Integrative Neurosciences, Colorado State University, Fort Collins, Colorado, United States of America.
  • Jorgensen ET; Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
  • Brown TE; Pharmaceutical Science and Neuroscience, University of Wyoming, Laramie, Wyoming, United States of America.
  • Elder JH; Pharmaceutical Science and Neuroscience, University of Wyoming, Laramie, Wyoming, United States of America.
  • Miller C; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
  • Hofmann F; Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
  • VandeWoude S; Technical University of Munich, Munich, Germany.
  • Kim S; Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
PLoS Biol ; 16(7): e2005315, 2018 07.
Article em En | MEDLINE | ID: mdl-30052626
ABSTRACT
Over half of individuals infected with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HANDs), yet the molecular mechanisms leading to neuronal dysfunction are poorly understood. Feline immunodeficiency virus (FIV) naturally infects cats and shares its structure, cell tropism, and pathology with HIV, including wide-ranging neurological deficits. We employ FIV as a model to elucidate the molecular pathways underlying HIV-induced neuronal dysfunction, in particular, synaptic alteration. Among HIV-induced neuron-damaging products, HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca2+ activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca2+ activity using intracellular Ca2+ imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca2+ activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca2+ by the activation of the endoplasmic reticulum (ER)-associated Ca2+ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. This suggests that HIV gp120 and FIV gp95 share a core pathological process in neurons. Significantly, gp95's stimulation of NMDARs activates cGMP-dependent protein kinase II (cGKII) through the activation of the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca2+ release from the ER and promotes surface expression of AMPA receptors, leading to an increase in synaptic activity. Moreover, we culture feline hippocampal neurons and confirm that gp95-induced neuronal Ca2+ overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca2+ hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sinapses / Síndrome de Imunodeficiência Adquirida Felina / HIV-1 / Vírus da Imunodeficiência Felina / Proteína Quinase Dependente de GMP Cíclico Tipo II Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sinapses / Síndrome de Imunodeficiência Adquirida Felina / HIV-1 / Vírus da Imunodeficiência Felina / Proteína Quinase Dependente de GMP Cíclico Tipo II Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article