HIV-1 Tat Protein Decreases Dopamine Transporter Cell Surface Expression and Vesicular Monoamine Transporter-2 Function in Rat Striatal Synaptosomes
Tóm tắt
The dopamine (DA) transporter (DAT) and vesicular monoamine transporter (VMAT2) proteins interact as a biochemical complex to regulate dopaminergic neurotransmission. We have reported that HIV-1Tat1–86 decreases the specific [3H]DA uptake and [3H]WIN 35,428 binding sites without a change in total DAT immunoreactivity in rat striatum (Zhu et al., 2009b). The present study determined the effects of Tat on DAT phosphorylation and trafficking, and vesicular [3H]DA uptake. Pre-incubation of rat striatal synaptosomes with the protein kinase C (PKC) inhibitor bisindolylmaleimide I (1 μM) completely blocked Tat1–86-induced reduction of [3H]DA uptake, indicating that Tat regulates DAT function through a PKC-dependent mechanism. After exposure of synaptosomes to Tat1–86 (1 μM), DAT immunoreactivity was decreased in plasma membrane enriched fractions (P3) and increased in vesicle-enriched fractions (P4) relative to controls without change in total synaptosomal fractions (P2), suggesting that Tat-induced inhibition of DA uptake is attributable to DAT internalization. Although both DAT and VMAT2 proteins are essential for the regulation of DA disposition in synapse and cytosol, Tat inhibited the specific [3H]DA uptake into vesicles (P4) and synaptosomes (P2) by 35 % and 26 %, respectively, inferring that the inhibitory effect of Tat was more profound in VMAT2 protein than in DAT protein. Taken together, the current study reveals that Tat inhibits DAT function through a PKC and trafficking-dependent mechanism and that Tat impacts the dopaminergic tone by regulating both DAT and VMAT2 proteins. These findings provide new insight into understanding the pharmacological mechanisms of HIV-1 viral protein-induced dysfunction of DA neurotransmission in HIV-infected patients.
Tài liệu tham khảo
Boudanova E, Navaroli DM, Melikian HE (2008) Amphetamine-induced decreases in dopamine transporter surface expression are protein kinase C-independent. Neuropharmacology 54:605–612
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Buch S, Yao H, Guo M, Mori T, Su TP, Wang J (2011) Cocaine and HIV-1 interplay: molecular mechanisms of action and addiction. J Neuroimmune Pharmacol 6:503–515
Campbell GR, Loret EP (2009) What does the structure-function relationship of the HIV-1 Tat protein teach us about developing an AIDS vaccine? Retrovirology 6:50
Cass WA, Harned ME, Peters LE, Nath A, Maragos WF (2003) HIV-1 protein Tat potentiation of methamphetamine-induced decreases in evoked overflow of dopamine in the striatum of the rat. Brain Res 984:133–142
Cervinski MA, Foster JD, Vaughan RA (2005) Psychoactive substrates stimulate dopamine transporter phosphorylation and down-regulation by cocaine-sensitive and protein kinase C-dependent mechanisms. J Biol Chem 280:40442–40449
Chang L, Wang GJ, Volkow ND, Ernst T, Telang F, Logan J, Fowler JS (2008) Decreased brain dopamine transporters are related to cognitive deficits in HIV patients with or without cocaine abuse. NeuroImage 42:869–878
Chen R, Furman CA, Gnegy ME (2010) Dopamine transporter trafficking: rapid response on demand. Futur Neurol 5:123
Chi L, Reith ME (2003) Substrate-induced trafficking of the dopamine transporter in heterologously expressing cells and in rat striatal synaptosomal preparations. J Pharmacol Exp Ther 307:729–736
Chudasama Y, Robbins TW (2006) Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans. Biol Psychol 73:19–38
Daniels GM, Amara SG (1999) Regulated trafficking of the human dopamine transporter. Clathrin-mediated internalization and lysosomal degradation in response to phorbol esters. J Biol Chem 274:35794–35801
Del Valle L, Croul S, Morgello S, Amini S, Rappaport J, Khalili K (2000) Detection of HIV-1 Tat and JCV capsid protein, VP1, in AIDS brain with progressive multifocal leukoencephalopathy. J Neurovirol 6:221–228
Egana LA, Cuevas RA, Baust TB, Parra LA, Leak RK, Hochendoner S, Pena K, Quiroz M, Hong WC, Dorostkar MM, Janz R, Sitte HH, Torres GE (2009) Physical and functional interaction between the dopamine transporter and the synaptic vesicle protein synaptogyrin-3. J Neurosci 29:4592–4604
Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E (1996) Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci U S A 93:5166–5171
Ernst T, Yakupov R, Nakama H, Crocket G, Cole M, Watters M, Ricardo-Dukelow ML, Chang L (2009) Declined neural efficiency in cognitively stable human immunodeficiency virus patients. Ann Neurol 65:316–325
Ferris MJ, Mactutus CF, Booze RM (2008) Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: current status of dopamine system vulnerability in NeuroAIDS. Neurosci Biobehav Rev 32:883–909
Fiala M, Gan XH, Zhang L, House SD, Newton T, Graves MC, Shapshak P, Stins M, Kim KS, Witte M, Chang SL (1998) Cocaine enhances monocyte migration across the blood–brain barrier. Cocaine’s connection to AIDS dementia and vasculitis? Adv Exp Med Biol 437:199–205
Fleckenstein A, Volz TJ, Riddle EL, Gibb JW, Hanson GR (2007) New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol 47:681–698
Fleckenstein AE, Volz TJ, Hanson GR (2009) Psychostimulant-induced alterations in vesicular monoamine transporter-2 function: neurotoxic and therapeutic implications. Neuropharmacology 56(Suppl 1):133–138
Furman CA, Chen R, Guptaroy B, Zhang M, Holz RW, Gnegy M (2009) Dopamine and amphetamine rapidly increase dopamine transporter trafficking to the surface: live-cell imaging using total internal reflection fluorescence microscopy. J Neurosci 29:3328–3336
Gorentla BK, Vaughan RA (2005) Differential effects of dopamine and psychoactive drugs on dopamine transporter phosphorylation and regulation. Neuropharmacology 49:759–768
Gu H, Wall SC, Rudnick G (1994) Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence. J Biol Chem 269:7124–7130
Gulley JM, Doolen S, Zahniser NR (2002) Brief, repeated exposure to substrates down-regulates dopamine transporter function in Xenopus oocytes in vitro and rat dorsal striatum in vivo. J Neurochem 83:400–411
Hu S, Sheng WS, Lokensgard JR, Peterson PK, Rock RB (2009) Preferential sensitivity of human dopaminergic neurons to gp120-induced oxidative damage. J Neurovirol 15:401–410
Hudson L, Liu J, Nath A, Jones M, Raghavan R, Narayan O, Male D, Everall I (2000) Detection of the human immunodeficiency virus regulatory protein tat in CNS tissues. J Neurovirol 6:145–155
Johnson RG Jr (1988) Accumulation of biological amines into chromaffin granules: a model for hormone and neurotransmitter transport. Physiol Rev 68:232–307
Johnson LA, Furman CA, Zhang M, Guptaroy B, Gnegy ME (2005) Rapid delivery of the dopamine transporter to the plasmalemmal membrane upon amphetamine stimulation. Neuropharmacology 49:750–758
Jones M, Olafson K, Del Bigio MR, Peeling J, Nath A (1998) Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) tat protein causes inflammation, gliosis, apoptosis, and ventricular enlargement. J Neuropathol Exp Neurol 57:563–570
Kass MD, Liu X, Vigorito M, Chang L, Chang SL (2010) Methamphetamine-induced behavioral and physiological effects in adolescent and adult HIV-1 transgenic rats. J Neuroimmune Pharmacol 5:566–573
Kumar AM, Fernandez JB, Singer EJ, Commins D, Waldrop-Valverde D, Ownby RL, Kumar M (2009) Human immunodeficiency virus type 1 in the central nervous system leads to decreased dopamine in different regions of postmortem human brains. J Neurovirol 15:257–274
Kumar AM, Ownby RL, Waldrop-Valverde D, Fernandez B, Kumar M (2011) Human immunodeficiency virus infection in the CNS and decreased dopamine availability: relationship with neuropsychological performance. J Neurovirol 17:26–40
Lamers SL, Salemi M, Galligan DC, Morris A, Gray R, Fogel G, Zhao L, McGrath MS (2010) Human immunodeficiency virus-1 evolutionary patterns associated with pathogenic processes in the brain. J Neurovirol 16:230–241
Larrat EP, Zierler S (1993) Entangled epidemics: cocaine use and HIV disease. J Psychoactive Drugs 25:207–221
Li W, Li G, Steiner J, Nath A (2009) Role of Tat protein in HIV neuropathogenesis. Neurotox Res 16:205–220
Lin Z, Itokawa M, Uhl GR (2000) Dopamine transporter proline mutations influence dopamine uptake, cocaine analog recognition, and expression. FASEB J 14:715–728
Ma M, Nath A (1997) Molecular determinants for cellular uptake of Tat protein of human immunodeficiency virus type 1 in brain cells. J Virol 71:2495–2499
Magnuson DS, Knudsen BE, Geiger JD, Brownstone RM, Nath A (1995) Human immunodeficiency virus type 1 tat activates non-N-methyl-D-aspartate excitatory amino acid receptors and causes neurotoxicity. Ann Neurol 37:373–380
McArthur JC, Steiner J, Sacktor N, Nath A (2010) Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann Neurol 67:699–714
McCune JM (2001) The dynamics of CD4+ T-cell depletion in HIV disease. Nature 410:974–979
Meade CS, Conn NA, Skalski LM, Safren SA (2011a) Neurocognitive impairment and medication adherence in HIV patients with and without cocaine dependence. J Behav Med 34:128–138
Meade CS, Lowen SB, MacLean RR, Key MD, Lukas SE (2011b) fMRI brain activation during a delay discounting task in HIV-positive adults with and without cocaine dependence. Psychiatry Res 192:167–175
Melikian HE (2004) Neurotransmitter transporter trafficking: endocytosis, recycling, and regulation. Pharmacol Ther 104:17–27
Middleton LS, Apparsundaram S, King-Pospisil KA, Dwoskin LP (2007) Nicotine increases dopamine transporter function in rat striatum through a trafficking-independent mechanism. Eur J Pharmacol 554:128–136
Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K, Schmitz Y, Krantz DE, Kobayashi K, Edwards RH, Sulzer D (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62:218–229
Nath A, Clements JE (2011) Eradication of HIV from the brain: reasons for pause. AIDS 25:577–580
Nath A, Conant K, Chen P, Scott C, Major EO (1999) Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem 274:17098–17102
New DR, Ma M, Epstein LG, Nath A, Gelbard HA (1997) Human immunodeficiency virus type 1 Tat protein induces death by apoptosis in primary human neuron cultures. J Neurovirol 3:168–173
Norman LR, Basso M, Kumar A, Malow R (2009) Neuropsychological consequences of HIV and substance abuse: a literature review and implications for treatment and future research. Curr Drug Abuse Rev 2:143–156
Perry SW, Barbieri J, Tong N, Polesskaya O, Pudasaini S, Stout A, Lu R, Kiebala M, Maggirwar SB, Gelbard HA (2010) Human immunodeficiency virus-1 Tat activates calpain proteases via the ryanodine receptor to enhance surface dopamine transporter levels and increase transporter-specific uptake and Vmax. J Neurosci 30:14153–14164
Richards TL, Zahniser NR (2009) Rapid substrate-induced down-regulation in function and surface localization of dopamine transporters: rat dorsal striatum versus nucleus accumbens. J Neurochem 108:1575–1584
Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, McArthur JC, Collier AC, Evans SR, Ellis RJ (2007) The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 21:1915–1921
Rudnick G, Clark J (1993) From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters. Biochim Biophys Acta 1144:249–263
Sager JJ, Torres GE (2011) Proteins interacting with monoamine transporters: current state and future challenges. Biochemistry 50:7295–7310
Sardar AM, Czudek C, Reynolds GP (1996) Dopamine deficits in the brain: the neurochemical basis of parkinsonian symptoms in AIDS. Neuroreport 7:910–912
Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, Lamb ME, Leeb-Lundberg LM, Carvelli L, Javitch JA, Galli A (2000) Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci U S A 97:6850–6855
Scheller C, Arendt G, Nolting T, Antke C, Sopper S, Maschke M, Obermann M, Angerer A, Husstedt IW, Meisner F, Neuen-Jacob E, Muller HW, Carey P, Ter Meulen V, Riederer P, Koutsilieri E (2010) Increased dopaminergic neurotransmission in therapy-naive asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses. J Neural Transm 117:699–705
Shan J, Javitch JA, Shi L, Weinstein H (2011) The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter. PLoS One 6:e16350
Silvers JM, Aksenova MV, Aksenov MY, Mactutus CF, Booze RM (2007) Neurotoxicity of HIV-1 Tat protein: involvement of D1 dopamine receptor. Neurotoxicology 28:1184–1190
Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A (1995) Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 15:4102–4108
Theodore S, Cass WA, Maragos WF (2006) Methamphetamine and human immunodeficiency virus protein Tat synergize to destroy dopaminergic terminals in the rat striatum. Neuroscience 137:925–935
Thwar PK, Guptaroy B, Zhang M, Gnegy ME, Burns MA, Linderman JJ (2007) Simple transporter trafficking model for amphetamine-induced dopamine efflux. Synapse 61:500–514
Tozzi V, Balestra P, Bellagamba R, Corpolongo A, Salvatori MF, Visco-Comandini U, Vlassi C, Giulianelli M, Galgani S, Antinori A, Narciso P (2007) Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors. J Acquir Immune Defic Syndr 45:174–182
Vergo S, Johansen JL, Leist M, Lotharius J (2007) Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels. Brain Res 1185:18–32
Volz TJ, Hanson GR, Fleckenstein AE (2007) The role of the plasmalemmal dopamine and vesicular monoamine transporters in methamphetamine-induced dopaminergic deficits. J Neurochem 101:883–888
Wallace DR, Dodson S, Nath A, Booze RM (2006) Estrogen attenuates gp120- and tat1-72-induced oxidative stress and prevents loss of dopamine transporter function. Synapse 59:51–60
Wang GJ, Chang L, Volkow ND, Telang F, Logan J, Ernst T, Fowler JS (2004) Decreased brain dopaminergic transporters in HIV-associated dementia patients. Brain 127:2452–2458
Webber MP, Schoenbaum EE, Gourevitch MN, Buono D, Klein RS (1999) A prospective study of HIV disease progression in female and male drug users. AIDS 13:257–262
Zahniser NR, Sorkin A (2004) Rapid regulation of the dopamine transporter: role in stimulant addiction? Neuropharmacology 47:80–91
Zhu J, Reith ME (2008) Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse. CNS Neurol Disord Drug Targets 7:393–409
Zhu J, Green T, Bardo MT, Dwoskin LP (2004) Environmental enrichment enhances sensitization to GBR 12935-induced activity and decreases dopamine transporter function in the medial prefrontal cortex. Behav Brain Res 148:107–117
Zhu J, Apparsundaram S, Bardo MT, Dwoskin LP (2005) Environmental enrichment decreases cell surface expression of the dopamine transporter in rat medial prefrontal cortex. J Neurochem 93:1434–1443
Zhu J, Apparsundaram S, Dwoskin LP (2009a) Nicotinic receptor activation increases [3H]dopamine uptake and cell surface expression of dopamine transporters in rat prefrontal cortex. J Pharmacol Exp Ther 328:931–939
Zhu J, Mactutus CF, Wallace DR, Booze RM (2009b) HIV-1 Tat protein-induced rapid and reversible decrease in [3H]dopamine uptake: dissociation of [3H]dopamine uptake and [3H]2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (WIN 35,428) binding in rat striatal synaptosomes. J Pharmacol Exp Ther 329:1071–1083
Zhu J, Ananthan S, Mactutus CF, Booze RM (2011) Recombinant HIV-1TAT(1–86) allosterically modulates dopamine transporter activity. Synapse.