Human Immunodeficiency Virus-1 Tat Activates Calpain Proteases via the Ryanodine Receptor to Enhance Surface Dopamine Transporter Levels and Increase Transporter-Specific Uptake and<i>V</i><sub>max</sub>

Perry, Seth W.; Barbieri, Justin; Tong, Ning; Polesskaya, Oksana; Pudasaini, Santosh; Stout, Angela; Lu, Rebecca; Kiebala, Michelle; Maggirwar, Sanjay B.; Gelbard, Harris A.

doi:10.1523/jneurosci.1042-10.2010

Cited by 51 publications

(57 citation statements)

References 104 publications

(162 reference statements)

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“…In DRG neurons, the increased excitability may partly result from an inhibition of Cdk5, although the concentration of Tat used (20 M) was much higher than used in our present study (100 nM). The 100 nM concentration was chosen for our studies from a range that elicited functional deficits in glia and neurons similar to those occurring in HIV-1 and that are considered to reflect levels seen under pathological conditions (Kruman et al, 1998;Nath et al, 1999;El-Hage et al, 2005Perry et al, 2010). In enteric neurons, we found that increased excitability is seen within 15 min and remains when examined in Tat transgenic mice following induction of the gene for over 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

Effects of HIV-1 Tat on Enteric Neuropathogenesis

Ngwainmbi

Smith

et al. 2014

J. Neurosci.

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The gastrointestinal (GI) tract presents a major site of immune modulation by HIV, resulting in significant morbidity. Most GI processes affected during HIV infection are regulated by the enteric nervous system. HIV has been identified in GI histologic specimens in up to 40% of patients, and the presence of viral proteins, including the trans-activator of transcription (Tat), has been reported in the gut indicating that HIV itself may be an indirect gut pathogen. Little is known of how Tat affects the enteric nervous system. Here we investigated the effects of the Tat protein on enteric neuronal excitability, proinflammatory cytokine release, and its overall effect on GI motility. Direct application of Tat (100 nM) increased the number of action potentials and reduced the threshold for action potential initiation in isolated myenteric neurons. This effect persisted in neurons pretreated with Tat for 3 d (19 of 20) and in neurons isolated from Tat ϩ (Tatexpressing) transgenic mice. Tat increased sodium channel isoforms Na v 1.7 and Na v 1.8 levels. This increase was accompanied by an increase in sodium current density and a leftward shift in the sodium channel activation voltage. RANTES, IL-6, and IL-1␤, but not TNF-␣, were enhanced by Tat. Intestinal transit and cecal water content were also significantly higher in Tat ϩ transgenic mice than Tat Ϫ littermates (controls). Together, these findings show that Tat has a direct and persistent effect on enteric neuronal excitability, and together with its effect on proinflammatory cytokines, regulates gut motility, thereby contributing to GI dysmotilities reported in HIV patients.

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Section: Discussionmentioning

confidence: 99%

Effects of HIV-1 Tat on Enteric Neuropathogenesis

Ngwainmbi

Smith

et al. 2014

J. Neurosci.

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“…Tat increases [Ca 2+ ] in by inducing Ca 2+ influx through Ca 2+ -permeable ion channels and release of intracellular Ca 2+ stores [49, 52–54]. This review seeks to summarize what is currently known about (i) Tat-mediated increases of Ca 2+ influx in neurons (mediated mainly by NMDAR, the L-channel and TRPC channel), (ii) Tat-mediated changes in intracellular Ca 2+ release, and (iii) the functional interplay of these channels, which could also be altered by Tat.…”

Section: Tat-mediated Dysregulation Of Ca2+ Influx and [Ca2+]in: Mmentioning

confidence: 99%

“…Third, Tat mediates increase of GSK-3β activity in rat cerebellar granule neurons [78] and midbrain primary neurons [54], and decrease of β-catenin activity in astrocytes [79, 80]. These changes are also associated with abnormal increases of [Ca 2+ ] in .…”

Section: Tat-mediated Dysregulation Of Ca2+ Influx and [Ca2+]in: Mmentioning

confidence: 99%

“…Whether this also occurs in neurons remains unknown and needs to be determined in future studies. In addition, Tat also induces rapid intracellular Ca 2+ release from the ER and mitochondria in cortical neurons, which appears to be mediated by RyR, independent of IP 3 R [52–54]. Abnormal RyR signaling induces the unfolded protein response (UPR) that leads to failure of mitochondrial energy metabolism (subsequent neuronal respiratory decline), which could cause death of neurons.…”

Section: Tat-mediated Dysregulation Of Ca2+ Influx and [Ca2+]in: Mmentioning

confidence: 99%

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HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions

2015

CDT

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Despite the success of combined antiretroviral therapy, more than half of HIV-1-infected patients in the USA show HIV-associated neurological and neuropsychiatric deficits. This is accompanied by anatomical and functional alterations in vulnerable brain regions of the mesocorticolimbic and nigrostriatal systems that regulate cognition, mood and motivation-driven behaviors, and could occur at early stages of infection. Neurons are not infected by HIV, but HIV-1 proteins (including but not limited to the HIV-1 trans-activator of transcription, Tat) induce Ca2+ dysregulation, indicated by abnormal and excessive Ca2+ influx and increased intracellular Ca2+ release that consequentially elevate cytosolic free Ca2+ levels ([Ca2+]in). Such alterations in intracellular Ca2+ homeostasis significantly disturb normal functioning of neurons, and induce dysregulation, injury, and death of neurons or non-neuronal cells, and associated tissue loss in HIV-vulnerable brain regions. This review discusses certain unique mechanisms, particularly the over-activation and/or upregulation of the ligand-gated ionotropic glutamatergic NMDA receptor (NMDAR), the voltage-gated L-type Ca2+ channel (L-channel) and the transient receptor potential canonical (TRPC) channel (a non-selective cation channel that is also permeable for Ca2+), which may underlie the deleterious effects of Tat on intracellular Ca2+ homeostasis and neuronal hyper-excitation that could ultimately result in excitotoxicity. This review also seeks to provide summarized information for future studies focusing on comprehensive elucidation of molecular mechanisms underlying the pathophysiological effects of Tat (as well as some other HIV-1 proteins and immunoinflammatory molecules) on neuronal function, particularly in HIV-vulnerable brain regions.

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“…The DAT is reduced in HIV patients, especially in those with cognitive/motor deficits [88]; DAT deficits correlate with cognitive/motor impairments [89]. As reported in our own and others work, DAT is directly targeted by HIV-1 proteins resulting in transporter impairment [91–97]. …”

Section: Pediatric Hiv/aids Infectionmentioning

confidence: 96%

HIV-1 Proteins, Tat and gp120, Target the Developing Dopamine System

Fitting¹,

Booze

Mactutus³

2015

CHR

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In 2014, 3.2 million children (< 15 years of age) were estimated to be living with HIV and AIDS worldwide, with the 240,000 newly infected children in the past year, i.e., another child infected approximately every two minutes [1]. The primary mode of HIV infection is through mother-to-child transmission (MTCT), occurring either in utero, intrapartum, or during breastfeeding. The effects of HIV-1 on the central nervous system (CNS) are putatively accepted to be mediated, in part, via viral proteins, such as Tat and gp120. The current review focuses on the targets of HIV-1 proteins during the development of the dopamine (DA) system, which appears to be specifically susceptible in HIV-1-infected children. Collectively, the data suggest that the DA system is a clinically relevant target in chronic HIV-1 infection, is one of the major targets in pediatric HIV-1 CNS infection, and may be specifically susceptible during development. The present review discusses the development of the DA system, follows the possible targets of the HIV-1 proteins during the development of the DA system, and suggests potential therapeutic approaches. By coupling our growing understanding of the development of the CNS with the pronounced age-related differences in disease progression, new light may be shed on the neurological and neurocognitive deficits that follow HIV-1 infection.

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Human Immunodeficiency Virus-1 Tat Activates Calpain Proteases via the Ryanodine Receptor to Enhance Surface Dopamine Transporter Levels and Increase Transporter-Specific Uptake andV_max

Cited by 51 publications

References 104 publications

Effects of HIV-1 Tat on Enteric Neuropathogenesis

Effects of HIV-1 Tat on Enteric Neuropathogenesis

HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions

HIV-1 Proteins, Tat and gp120, Target the Developing Dopamine System

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Human Immunodeficiency Virus-1 Tat Activates Calpain Proteases via the Ryanodine Receptor to Enhance Surface Dopamine Transporter Levels and Increase Transporter-Specific Uptake andVmax

Cited by 51 publications

References 104 publications

Effects of HIV-1 Tat on Enteric Neuropathogenesis

Effects of HIV-1 Tat on Enteric Neuropathogenesis

HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions

HIV-1 Proteins, Tat and gp120, Target the Developing Dopamine System

Contact Info

Product

Resources

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Human Immunodeficiency Virus-1 Tat Activates Calpain Proteases via the Ryanodine Receptor to Enhance Surface Dopamine Transporter Levels and Increase Transporter-Specific Uptake andV_max