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  • 1.
    Cairns, Andrew G.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Vazquez-Romero, Ana
    Mahdi-Moein, Mohammad
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Elmore, Charles S.
    Takano, Akihiro
    Arakawa, Ryosuke
    Varrone, Andrea
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Schou, Magnus
    Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy2018Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 9, nr 11, s. 2542-2547Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C (t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain.

  • 2. Gruden, Marina A.
    et al.
    Davydova, Tatiana V.
    Kudrin, Vladimir S.
    Wang, Chao
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Narkevich, Victor B.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sewell, Robert D. E.
    S100A9 Protein Aggregates Boost Hippocampal Glutamate Modifying Monoaminergic Neurochemistry: A Glutamate Antibody Sensitive Outcome on Alzheimer-like Memory Decline2018Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 9, nr 3, s. 568-577Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer's disease (AD) involves dementia conceivably arising from integrated inflammatory processes, amyloidogenesis, and neuronal apoptosis. Glutamate can also cause neuronal death via excitotoxicity, and this is similarly implicated in some neurological diseases. The aim was to examine treatment with in vitro generated proinflammatory protein S100A9 aggregate species alone or with glutamate antibodies (Glu-Abs) on Morris water maze (MWM) spatial learning and memory performance in 12 month old mice. Amino acid and monoamine cerebral neurotransmitter metabolic changes were concurrently monitored. Initially, S100A9 fibrils were morphologically verified by atomic force microscopy and Thioflavin T assay. They were then administered intranasally alone or with Glu-Abs for 14 days followed by a 5 day MWM protocol before hippocampal and prefrontal cortical neurochemical analysis. S100A9 aggregates evoked spatial amnesia which correlated with disrupted glutamate and dopaminergic neurochemistry. Hippocampal glutamate release, elevation of DOPAC and HVA, as well as DOPAC/DA and HVA/DA ratios were subsequently reduced by Glu-Abs which simultaneously prevented the spatial memory deficit. The present outcomes emphasized the pathogenic nature of S100A9 fibrillar aggregates in causing spatial memory amnesia associated with enhanced hippocampal glutamate release and DA-ergic disruption in the aging brain. This finding might be exploited during dementia management through a neuroprotective strategy.

  • 3.
    Horvath, Istvan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iashchishyn, Igor A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of General Chemistry, Sumy State University, Ukraine.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Immunochemical Detection of alpha-Synuclein Autoantibodies in Parkinson's Disease: Correlation between Plasma and Cerebrospinal Fluid Levels2017Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 8, nr 6, s. 1170-1176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autoantibodies to Parkinson's disease (PD) amyloidogenic protein, a-synuclein, were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 individuals, including recently diagnosed PD patients with mild and moderate PD and age-matched controls, were examined by enzyme-linked immunosorbent assay (ELISA). Nonparametric statistics was used for data analysis. We found significantly elevated levels of a-synuclein autoantibodies in both plasma and CSF in mild PD compared to controls, followed by some decrease in moderate PD. Receiver operating characteristic and effect size analyses confirmed the diagnostic power of a-synuclein antibodies in both plasma and CSF. For the first time, we showed the correlation between plasma and CSF a-synuclein antibody levels for mild, moderate, and combined PD groups. This indicates the potentiality of a-synuclein antibodies as PD biomarker and the increased diagnostic power of their simultaneous analysis in plasma and CSF.

  • 4.
    Horvath, Istvan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Jia, Xueen
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Johansson, Per
    Wang, Chao
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Moskalenko, Roman
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of Pathology, Sumy State University, Sumy 40000, Ukraine.
    Steinau, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Wågberg, Thomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik.
    Svensson, Johan
    Zetterberg, Henrik
    Morozova-Roche, Ludmilla A
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease2016Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 7, nr 1, s. 34-39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pro-inflammatory protein S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ1-42 and tau-proteins. CSF samples from 104 stringently diagnosed individuals divided into five subgroups were analyzed, including nondemented controls, stable mild cognitive impairment (SMCI), mild cognitive impairment due to Alzheimer's disease (MCI-AD), Alzheimer's disease (AD), and vascular dementia (VaD) patients. ELISA, dot-blotting, and electrochemical impedance spectroscopy were used as research methods. The S100A9 and Aβ1-42 levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCI-AD, AD, and VaD conditions. Immunohistochemical analysis also revealed involvement of both Aβ1-42 and S100A9 in the amyloid-neuroinflammatory cascade already during SMCI. Tau proteins were not yet altered in SMCI; however their contents increased during MCI-AD and AD, diagnosing later dementia stages. Thus, four biomarkers together, reflecting different underlying pathological causes, can accurately differentiate dementia progression and also distinguish AD from VaD.

  • 5.
    Iashchishyn, Igor A.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of General Chemistry, Sumy State University, Sumy, Ukraine.
    Gruden, Marina A.
    Moskalenko, Roman A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of Pathology, Sumy State University, Sumy, Ukraine .
    Davydova, Tatiana, V
    Wang, Chao
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sewell, Robert D. E.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Intranasally Administered S100A9 Amyloids Induced Cellular Stress, Amyloid Seeding, and Behavioral Impairment in Aged Mice2018Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 9, nr 6, s. 1338-1348Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyloid formation and neuroinflammation are major features of Alzheimer's disease pathology. Proinflammatory mediator S100A9 was shown to act as a link between the amyloid and neuroinflammatory cascades in Alzheimer's disease, leading together with Aβ to plaque formation, neuronal loss and memory impairment. In order to examine if S100A9 alone in its native and amyloid states can induce neuronal stress and memory impairment, we have administered S100A9 species intranasally to aged mice. Single and sequential immunohistochemistry and passive avoidance behavioral test were conducted to evaluate the consequences. Administered S100A9 species induced widespread cellular stress responses in cerebral structures, including frontal lobe, hippocampus and cerebellum. These were manifested by increased levels of S100A9, Box, and to a lesser extent activated caspase-3 immunopositive cells. Upon administration of S100A9 fibrils, the amyloid oligomerization was observed in the brain tissues, which can further exacerbate cellular stress. The cellular stress responses correlated with significantly increased training and decreased retention latencies measured in the passive avoidance test for the SI00A9 treated animal groups. Remarkably, the effect size in the behavioral tests was moderate already in the group treated with native S100A9, while the effect sizes were large in the groups administered S100A9 amyloid oligomers or fibrils. The findings demonstrate the brain susceptibility to neurotoxic damage of S100A9 species leading to behavioral and memory impairments. Intranasal administration of S100A9 species proved to be an effective method to study amyloid induced brain dysfunctions, and 5100A9 itself may be postulated as a target to allay early stage neurodegenerative and neuroinflammatory processes.

  • 6.
    Iashchishyn, Igor A.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of General Chemistry, Sumy State University, Sumy, Ukraine.
    Sulskis, Darius
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
    Ngoc, Mai Nguyen
    Smirnovas, Vytautas
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Finke-Watzky Two-Step Nucleation-Autocatalysis Model of S100A9 Amyloid Formation: Protein Misfolding as "Nucleation" Event2017Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 8, nr 10, s. 2152-2158Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Quantitative kinetic analysis is critical for understanding amyloid mechanisms. Here we demonstrate the application of generic Finke-Watzky (F-W) two-step nucleation-autocatalytic growth model to the concentration-dependent amyloid kinetics of proinflammatory alpha-helical S100A9 protein at pH 7.4 and at 37 and 42 degrees C. The model is based on two pseudoelementary reaction steps applied without further analytical constraints, and its treatment of S100A9 amyloid self-assembly demonstrates that initial misfolding and beta-sheet formation, defined as "nucleation" step, spontaneously takes place within individual S100A9 molecules at higher rate than the subsequent fibrillar growth. The latter, described as an autocatalytic process, will proceed if misfolded amyloid-prone S100A9 is populated on a macroscopic time scale. Short lengths of S100A9 fibrils are consistent with the F-W model. The analysis of fibrillar length distribution by the Beker-Doring model demonstrates independently that such distribution is solely determined by slow fibril growth and there is no fragmentation or secondary pathways decreasing fibrillar length.

  • 7.
    Leri, Manuela
    et al.
    Department of Experimental and Clinical Biomedical Sciences "mario Serio", University of Florence, Florence, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
    Chaudhary, Himanshu
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Iashchishyn, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pansieri, Jonathan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Svedružić, Željko M.
    Department of Biotechnology, University of Rijeka, Rijeka, Croatia.
    Gómez Alcalde, Silvia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Musteikyte, Greta
    Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
    Smirnovas, Vytautas
    Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
    Stefani, Massimo
    Department of Experimental and Clinical Biomedical Sciences "mario Serio", University of Florence, Florence, Italy.
    Bucciantini, Monica
    Department of Experimental and Clinical Biomedical Sciences "mario Serio", University of Florence, Florence, Italy.
    Morozova-Roche, Ludmilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Natural Compound from Olive Oil Inhibits S100A9 Amyloid Formation and Cytotoxicity: Implications for Preventing Alzheimer's Disease2021Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 12, nr 11, s. 1905-1918Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polyphenolic compounds in the Mediterranean diet have received increasing attention due to their protective properties in amyloid neurodegenerative and many other diseases. Here, we have demonstrated for the first time that polyphenol oleuropein aglycone (OleA), which is the most abundant compound in olive oil, has multiple potencies for the inhibition of amyloid self-assembly of pro-inflammatory protein S100A9 and the mitigation of the damaging effect of its amyloids on neuroblastoma SH-SY5Y cells. OleA directly interacts with both native and fibrillar S100A9 as shown by intrinsic fluorescence and molecular dynamic simulation. OleA prevents S100A9 amyloid oligomerization as shown using amyloid oligomer-specific antibodies and cross-β-sheet formation detected by circular dichroism. It decreases the length of amyloid fibrils measured by atomic force microscopy (AFM) as well as reduces the effective rate of amyloid growth and the overall amyloid load as derived from the kinetic analysis of amyloid formation. OleA disintegrates already preformed fibrils of S100A9, converting them into nonfibrillar and nontoxic aggregates as revealed by amyloid thioflavin-T dye binding, AFM, and cytotoxicity assays. At the cellular level, OleA targets S100A9 amyloids already at the membranes as shown by immunofluorescence and fluorescence resonance energy transfer, significantly reducing the amyloid accumulation in GM1 ganglioside containing membrane rafts. OleA increases overall cell viability when neuroblastoma cells are subjected to the amyloid load and alleviates amyloid-induced intracellular rise of reactive oxidative species and free Ca2+. Since S100A9 is both a pro-inflammatory and amyloidogenic protein, OleA may effectively mitigate the pathological consequences of the S100A9-dependent amyloid-neuroinflammatory cascade as well as provide protection from neurodegeneration, if used within the Mediterranean diet as a potential preventive measure.

  • 8.
    Naaman, Efrat
    et al.
    Department of Ophthalmology, Rambam Health Care Campus, Haifa, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel.
    Qarawani, Amanda
    Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
    Ben-Zvi Elimelech, Rony
    Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
    Harel, Michal
    Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
    Sigal-Dror, Shahaf
    Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
    Safuri, Shadi
    Department of Ophthalmology, Rambam Health Care Campus, Haifa, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel.
    Smirnovas, Vytautas
    Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
    Baronaite, Ieva
    Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
    Romanova, Nina V.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zayit-Soudry, Shiri
    Department of Ophthalmology, Rambam Health Care Campus, Haifa, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
    The surprising nonlinear effects of S100A9 proteins in the retina2024Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 15, nr 4, s. 735-744Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Age-related macular degeneration (AMD) is a complex disease in which inflammation is implicated as a key factor but the precise molecular mechanisms are poorly understood. AMD lesions contain an excess of the pro-inflammatory S100A9 protein, but its retinal significance was yet unexplored. S100A9 was shown to be intrinsically amyloidogenic in vitro and in vivo. Here, we hypothesized that the retinal effects of S100A9 are related to its supramolecular conformation. ARPE-19 cultures were treated with native dimeric and fibrillar S100A9 preparations, and cell viability was determined. Wild-type rats were treated intravitreally with the S100A9 solutions in the right eye and with the vehicle in the left. Retinal function was assessed longitudinally by electroretinography (ERG), comparing the amplitudes and configurations for each intervention. Native S100A9 had no impact on cellular viability in vitro or on the retinal function in vivo. Despite dispersed intracellular uptake, fibrillar S100A9 did not decrease ARPE-19 cell viability. In contrast, S100A9 fibrils impaired retinal function in vivo following intravitreal injection in rats. Intriguingly, low-dose fibrillar S100A9 induced contrasting in vivo effects, significantly increasing the ERG responses, particularly over 14 days postinjection. The retinal effects of S100A9 were further characterized by glial and microglial cell activation. We provide the first indication for the retinal effects of S100A9, showing that its fibrils inflicted retinal dysfunction and glial activation in vivo, while low dose of the same assemblies resulted in an unpredicted enhancement of the ERG amplitudes. These nonlinear responses highlight the consequences of self-assembly of S100A9 and provide insight into its pathophysiological and possibly physiological roles in the retina.

  • 9. Tian, Yin
    et al.
    Cao, Rui
    Che, Bingchen
    Sun, Dan
    Tang, Yong
    Jiang, Lin
    Bai, Qiao
    Liu, Yonggang
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zhang, Ce
    Proinflammatory S100A9 Regulates Differentiation and Aggregation of Neural Stem Cells2020Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 11, nr 21, s. 3549-3556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inflammation is the primary pathological feature of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease. Proinflammatory molecules (e.g., S100A9) play important roles during the progression of the diseases by regulating behavior and fate of multiple cell types in the nervous system. Our earlier studies reveal that S100A9 is toxic to neurons, and its interaction with Aβ peptides leads to the formation of large nontoxic amyloidogenic aggregates, suggesting a protective role of coaggregation with Aβ amyloids. We herein demonstrate that S100A9 interacts with neural stem cells (NSCs) and causes NSC differentiation. In the brain of transgenic AD mouse models, we found large quantities of proinflammatory S100A9, which colocalizes with the differentiated NSCs. NSC sphere formation, which is a representative character of NSC stemness, is also substantially inhibited by S100A9. These results suggest that S100A9 is a representative marker for the inflammatory conditions in AD, and it promotes NSC differentiation. Intriguingly, in contrast to the death of both stem and differentiated NSCs caused by high S100A9 doses, S100A9 at a moderate concentration is toxic only to the early differentiated NSCs but not the stem cells. We therefore postulate that, at the early stage of AD, the expression of S100A9 leads to NSC differentiation, which remedies the neuron damage. The application of drugs, which help maintain NSC stemness (e.g., the platelet-derived growth factor, PDGF), may help overcome the acute inflammatory conditions and improve the efficacy of NSC transplantation therapy.

  • 10. Wesen, Emelie
    et al.
    Lundmark, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Esbjörner, Elin K.
    Role of Membrane Tension Sensitive Endocytosis and Rho GTPases in the Uptake of the Alzheimer’s Disease Peptide Aβ(1-42)2020Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 11, nr 13, s. 1925-1936Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intraneuronal accumulation of amyloid-β (Aβ) is an early pathological signum of Alzheimer’s disease, and compartments of the endolysosomal system have been implicated in both seeding and cell–cell propagation of Aβ aggregation. We have studied how clathrin-independent mechanisms contribute to Aβ endocytosis, exploring pathways that are sensitive to changes in membrane tension and the regulation of Rho GTPases. Using live cell confocal microscopy and flow cytometry, we show the uptake of monomeric Aβ(1-42) into endocytic vesicles and vacuole-like dilations, following relaxation of osmotic pressure-induced cell membrane tension. This indicates Aβ(1-42) uptake via clathrin independent carriers (CLICs), although overexpression of the bar-domain protein GRAF1, a key regulator of CLICs, had no apparent effect. We furthermore report reduced Aβ(1-42) uptake following overexpression of constitutively active forms of the Rho GTPases Cdc42 and RhoA, whereas modulation of Rac1, which is linked to macropinosome formation, had no effect. Our results confirm that uptake of Aβ(1-42) is clathrin- and dynamin-independent and point to the involvement of a new and distinct clathrin-independent endocytic mechanism which is similar to uptake via CLICs or macropinocytosis but that also appear to involve yet uncharacterized molecular players.

  • 11.
    Yoluk, Özge
    et al.
    KTH, Science for Life Laboratory, SciLifeLab.
    Lindahl, Erik
    KTH, Science for Life Laboratory, SciLifeLab.
    Andersson, Magnus
    Science for Life Laboratory; Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, Stockholm, Sweden.
    Conformational Gating Dynamics in the GluCl Anion-Selective Chloride Channel2015Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 6, nr 8, s. 1459-1467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cys-loop receptors are central to propagation of signals in the nervous system. The gating of the membrane-spanning pore is triggered by structural rearrangements in the agonist-binding site, located some so A away from the pore. A sequential conformational change, propagating from the ligand-binding site to the pore, has been proposed to govern gating in all Cys-loop receptors. Here, we identify structural and dynamic components of the conformational gating in the eukaryotic glutamate-gated chloride channel (GluCl) by means of molecular dynamics (MD) simulations with and without the L-glutamate agonist bound. A significant increase in pore opening and accompanying hydration is observed in the presence of glutamate. Potential of mean force calculations reveal that the barrier for ion passage drops from 15 kcal/mol to 5-10 kcal/mol with the agonist bound. This appears to be explained by agonist binding that leads to significant changes in the intersubunit hydrogen-bonding pattern, which induce a slight tilt of the extracellular domain relative to the transmembrane domain in the simulations. This rearrangement is subtle, but correspond to the direction of the quaternary twist observed as a key difference between open and closed X-ray structures. While the full reversible gating is still a much slower process, the observed structural dynamics sheds new light on the early stages of how the agonist influences the extracellular domain, how the extracellular domain interacts with the transmembrane domain, and how changes in the transmembrane domain alter the free energy of ion passage.

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  • 12. Ågren, Richard
    et al.
    Zeberg, Hugo
    Stępniewski, Tomasz Maciej
    Free, R. Benjamin
    Reilly, Sean W.
    Luedtke, Robert R.
    Arhem, Peter
    Ciruela, Francisco
    Sibley, David R.
    Mach, Robert H.
    Selent, Jana
    Nilsson, Johanna
    Sahlholm, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Ligand with Two Modes of Interaction with the Dopamine D-2 Receptor-An Induced-Fit Mechanism of Insurmountable Antagonism2020Ingår i: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 11, nr 19, s. 3130-3143Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A solid understanding of the mechanisms governing ligand binding is crucial for rational design of therapeutics targeting the dopamine D2 receptor (D2R). Here, we use G protein-coupled inward rectifier potassium (GIRK) channel activation in Xenopus oocytes to measure the kinetics of D2R antagonism by a series of aripiprazole analogues, as well as the recovery of dopamine (DA) responsivity upon washout. The aripiprazole analogues comprise an orthosteric and a secondary pharmacophore and differ by the length of the saturated carbon linker joining these two pharmacophores. Two compounds containing 3- and 5-carbon linkers allowed for a similar extent of recovery from antagonism in the presence of 1 or 100 μM DA (>25 and >90% of control, respectively), whereas recovery was less prominent (∼20%) upon washout of the 4-carbon linker compound, SV-III-130, both with 1 and 100 μM DA. Prolonging the coincubation time with SV-III-130 further diminished recovery. Curve-shift experiments were consistent with competition between SV-III-130 and DA. Two mutations in the secondary binding pocket (V91A and E95A) of D2R decreased antagonistic potency and increased recovery from SV-III-130 antagonism, whereas a third mutation (L94A) only increased recovery. Our results suggest that the secondary binding pocket influences recovery from inhibition by the studied aripiprazole analogues. We propose a mechanism, supported by in silico modeling, whereby SV-III-130 initially binds reversibly to the D2R, after which the drug-receptor complex undergoes a slow transition to a second ligand-bound state, which is dependent on secondary binding pocket integrity and irreversible during the time frame of our experiments.

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