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HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model

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 structu...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082575/
https://www.ncbi.nlm.nih.gov/pubmed/30052626
http://dx.doi.org/10.1371/journal.pbio.2005315
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author 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
author_facet 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
author_sort Sztukowski, Keira
collection PubMed
description 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 Ca(2+) activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca(2+) activity using intracellular Ca(2+) imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca(2+) activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca(2+) by the activation of the endoplasmic reticulum (ER)-associated Ca(2+) 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 Ca(2+) 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 Ca(2+) overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca(2+) hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.
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spelling pubmed-60825752018-08-28 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 PLoS Biol Research Article 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 Ca(2+) activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca(2+) activity using intracellular Ca(2+) imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca(2+) activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca(2+) by the activation of the endoplasmic reticulum (ER)-associated Ca(2+) 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 Ca(2+) 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 Ca(2+) overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca(2+) hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND. Public Library of Science 2018-07-27 /pmc/articles/PMC6082575/ /pubmed/30052626 http://dx.doi.org/10.1371/journal.pbio.2005315 Text en © 2018 Sztukowski et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
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
HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model
title HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model
title_full HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model
title_fullStr HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model
title_full_unstemmed HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model
title_short HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model
title_sort hiv induces synaptic hyperexcitation via cgmp-dependent protein kinase ii activation in the fiv infection model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082575/
https://www.ncbi.nlm.nih.gov/pubmed/30052626
http://dx.doi.org/10.1371/journal.pbio.2005315
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