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HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization.

ABSTRACT: Neurologic disease caused by human immunodeficiency virus type 1 (HIV-1) is ultimately refractory to highly active antiretroviral therapy (HAART) because of failure of complete virus eradication in the central nervous system (CNS), and disruption of normal neural signaling events by virally induced chronic neuroinflammation. We have previously reported that HIV-1 Tat can induce mitochondrial hyperpolarization in cortical neurons, thus compromising the ability of the neuron to buffer calcium and sustain energy production for normal synaptic communication. In this report, we demonstrate that Tat induces rapid loss of ER calcium mediated by the ryanodine receptor (RyR), followed by the unfolded protein response (UPR) and pathologic dilatation of the ER in cortical neurons in vitro. RyR antagonism attenuated both Tat-mediated mitochondrial hyperpolarization and UPR induction. Delivery of Tat to murine CNS in vivo also leads to long-lasting pathologic ER dilatation and mitochondrial morphologic abnormalities. Finally, we performed ultrastructural studies that demonstrated mitochondria with abnormal morphology and dilated endoplasmic reticulum (ER) in brain tissue of patients with HIV-1 inflammation and neurodegeneration. Collectively, these data suggest that abnormal RyR signaling mediates the neuronal UPR with failure of mitochondrial energy metabolism, and is a critical locus for the neuropathogenesis of HIV-1 in the CNS.

SUBMITTER: Norman JP

PROVIDER: S-EPMC2579580 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization.

Norman John P JP Perry Seth W SW Reynolds Holly M HM Kiebala Michelle M De Mesy Bentley Karen L KL Trejo Margarita M Volsky David J DJ Maggirwar Sanjay B SB Dewhurst Stephen S Masliah Eliezer E Gelbard Harris A HA

PloS one 20081114 11

Neurologic disease caused by human immunodeficiency virus type 1 (HIV-1) is ultimately refractory to highly active antiretroviral therapy (HAART) because of failure of complete virus eradication in the central nervous system (CNS), and disruption of normal neural signaling events by virally induced chronic neuroinflammation. We have previously reported that HIV-1 Tat can induce mitochondrial hyperpolarization in cortical neurons, thus compromising the ability of the neuron to buffer calcium and ...[more]

PMID: 19009018

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Project description:Calcium ion dyshomeostasis contributes to the progression of many neurodegenerative diseases and represents a target for the development of neuroprotective therapies, as reported by Duncan et al. (Molecules 15(3):1168-95, 2010), LaFerla (Nat Rev Neurosci 3(11):862-72, 2002), and Niittykoshi et al. (Invest Ophthalmol Vis Sci 51(12):6387-93, 2010). Dysfunctional ryanodine receptors contribute to calcium ion dyshomeostasis and potentially to the pathogenesis of neurodegenerative diseases by generating abnormal calcium ion release from the endoplasmic reticulum, according to Bruno et al. (Neurobiol Aging 33(5):1001 e1-6, 2012) and Stutzmann et al. (J Neurosci 24(2):508-13, 2004). Since ryanodine receptors share functional and structural similarities with potassium channels, as reported by Lanner et al. (Cold Spring Harb Perspect Biol 2(11):a003996, 2010), and small molecules with anti-oxidant properties, such as resveratrol (3,5,4'-trihydroxy-trans-stilbene), directly control the activity of potassium channels, according to Wang et al. (J Biomed Sci 23(1):47, 2016), McCalley et al. (Molecules 19(6):7327-40, 2014), Novakovic et al. (Mol Hum Reprod 21(6):545-51, 2015), Li et al. (Cardiovasc Res 45(4):1035-45, 2000), Gopalakrishnan et al. (Br J Pharmacol 129(7):1323-32, 2000), and Hambrock et al. (J Biol Chem 282(5):3347-56, 2007), we hypothesized that trans-resveratrol can modulate intracellular calcium signaling through direct binding and functional regulation of ryanodine receptors. The goal of our study was to identify and measure the control of ryanodine receptor activity by trans-resveratrol. Mechanisms of calcium signaling mediated by the direct interaction between trans-resveratrol and ryanodine receptors were identified and measured with single-channel electrophysiology. Addition of trans-resveratrol to the cytoplasmic face of the ryanodine receptor increased single-channel activity at physiological and elevated pathophysiological cytoplasmic calcium ion concentrations. The open probability of the channel increases after interacting with the small molecule in a dose-dependent manner, but remains also dependent on the concentration of its physiological ligand, cytoplasmic-free calcium ions. This study provides the first evidence of a direct functional interaction between trans-resveratrol and ryanodine receptors. Such functional control of ryanodine receptors by trans-resveratrol as a novel mechanism of action could provide additional rationales for the development of novel therapeutic strategies to treat and prevent neurodegenerative diseases.

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HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization.

Publications

HIV-1 Tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization.

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