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Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines
Department of Woman and Child Health, Karolinska Institutet.
Department of Woman and Child Health, Karolinska Institutet.
Department of Woman and Child Health, Karolinska Institutet.
KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
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2006 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 3, 762-767 p.Article in journal (Refereed) Published
Abstract [en]

The dopaminergic and glutamatergic systems interact to initiate and organize normal behavior, a communication that may be perturbed in many neuropsychiatric diseases, including schizophrenia. We show here that NMDA, by allosterically modifying NMDA receptors, can act as a scaffold to recruit laterally diffusing dopamine D1 receptors (D1R) to neuronal spines. Using organotypic culture from rat striatum transfected with D1R fused to a fluorescent protein, we show that the majority of dendritic D1R are in lateral diffusion and that their mobility is confined by interaction with NMDA receptors. Exposure to NMDA reduces the diffusion coefficient for D1R and causes an increase in the number of D1R-positive spines. Unexpectedly, the action of NMDA in potentiating D1R recruitment was independent of calcium flow via the NMDA receptor channel. Thus, a highly energy-efficient, diffusion-trap mechanism can account for intraneuronal interaction between the glutamatergic and dopaminergic systems and for regulation of the number of D1R-positive spines. This diffusion trap system represents a molecular mechanism for brain plasticity and offers a promising target for development of antipsychotic therapy

Place, publisher, year, edition, pages
2006. Vol. 103, no 3, 762-767 p.
Keyword [en]
Fluorescence recovery after photo-bleaching; Lateral diffusion; Organotypic cultures; Receptor movement
National Category
Condensed Matter Physics
Identifiers
URN: urn:nbn:se:kth:diva-7063DOI: 10.1073/pnas.0505557103ISI: 000234727800047Scopus ID: 2-s2.0-31444439409OAI: oai:DiVA.org:kth-7063DiVA: diva2:11959
Note
QC 20100726Available from: 2007-05-08 Created: 2007-05-08 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Mathematical Models in Cellular Biophysics
Open this publication in new window or tab >>Mathematical Models in Cellular Biophysics
2007 (English)Licentiate thesis, comprehensive summary (Other scientific)
Abstract [en]

Cellular biophysics deals with, among other things, transport processes within cells. This thesis presents two studies where mathematical models have been used to explain how two of these processes occur.

Cellular membranes separate cells from their exterior environment and also divide a cell into several subcellular regions. Since the 1970s lateral diffusion in these membranes has been studied, one the most important experimental techniques in these studies is fluorescence recovery after photobleach (FRAP). A mathematical model developed in this thesis describes how dopamine 1 receptors (D1R) diffuse in a neuronal dendritic membrane. Analytical and numerical methods have been used to solve the partial differential equations that are expressed in the model. The choice of method depends mostly on the complexity of the geometry in the model.

Calcium ions (Ca2+) are known to be involved in several intracellular signaling mechanisms. One interesting concept within this field is a signaling microdomain where the inositol 1,4,5-triphosphate receptor (IP3R) in the endoplasmic reticulum (ER) membrane physically interacts with plasma membrane proteins. This microdomain has been shown to cause the intracellular Ca2+ level to oscillate. The second model in this thesis describes a signaling network involving both ER membrane bound and plasma membrane Ca2+ channels and pumps, among them store-operated Ca2+ (SOC) channels. A MATLAB® toolbox was developed to implement the signaling networks and simulate its properties. This model was also implemented using Virtual cell.

The results show a high resemblance between the mathematical model and FRAP data in the D1R study. The model shows a distinct difference in recovery characteristics of simulated FRAP experiments on whole dendrites and dendritic spines, due to differences in geometry. The model can also explain trapping of D1R in dendritic spines.

The results of the Ca2+ signaling model show that stimulation of IP3R can cause Ca2+ oscillations in the same frequency range as has been seen in experiments. The removing of SOC channels from the model can alter the characteristics as well as qualitative appearance of Ca2+ oscillations.

Abstract [sv]

Cellulär biofysik behandlar bland annat transportprocesser i celler. I denna avhandling presenteras två studier där matematiska modeller har använts för att förklara hur två av dess processer uppkommer.

Cellmembran separerar celler från deras yttre miljö och delar även upp en cell i flera subcellulära regioner. Sedan 1970-talet har lateral diffusion i dessa membran studerats, en av de viktigaste experimentella metoderna i dessa studier är fluorescence recovery after photobleach (FRAP). En matematisk modell utvecklad i denna avhandling beskriver hur dopamin 1-receptorer (D1R) diffunderar i en neural dendrits membran. Analytiska och numeriska metoder har använts för att lösa de partiella differentialekvationer som uttrycks i modellen. Valet av metod beror främst på komplexiteten hos geometrin i modellen.

Kalciumjoner (Ca2+) är kända för att ingå i flera intracellulära signalmekanismer. Ett intressant koncept inom detta fält är en signalerande mikrodomän där inositol 1,4,5-trifosfatreceptorn (IP3R) i endoplasmatiska nätverksmembranet (ER-membranet) fysiskt interagerar med proteiner i plasmamembranet. Denna mikrodomän har visats vara orsak till oscillationer i den intracellulära Ca2+-nivån. Den andra modellen i denna avhandling beskriver ett signalerande nätverk där både Ca2+-kanaler och pumpar bundna i ER-membranet och i plasmamembranet, däribland store-operated Ca2+(SOC)-kanaler, ingår. Ett MATLAB®-verktyg utvecklades för att implementera signalnätverket och simulera dess egenskaper. Denna modell implementerades även i Virtual cell.

Resultaten visar en stark likhet mellan den matematiska modellen och FRAP-datat i D1R-studien. Modellen visar en distinkt skillnad i återhämtningsegenskaper hos simulerade FRAP-experiment på hela dendriter och dendritiska spines, beroende på skillnader i geometri. Modellen kan även förklara infångning av D1R i dendritiska spines.

Resultaten från Ca2+-signaleringmodellen visar att stimulering av IP3R kan orsaka Ca2+-oscillationer inom samma frekvensområde som tidigare setts i experiment. Att ta bort SOC-kanaler från modellen kan ändra karaktär hos, såväl som den kvalitativa uppkomsten av Ca2+-oscillationer.

Place, publisher, year, edition, pages
Stockholm: KTH, 2007. v, 50 p.
Series
Trita-FYS, ISSN 0280-316X ; 2007:33
Keyword
Calcium oscillations, Diffusion, Dopamine receptors, Mathematical models, Computer simulations, FRAP
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-4361 (URN)978-91-7178-660-9 (ISBN)
Presentation
2007-05-22, FA32, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20101111Available from: 2007-05-08 Created: 2007-05-08 Last updated: 2010-11-11Bibliographically approved
2. Modeling and Data Analysis in Cellular Biophysics
Open this publication in new window or tab >>Modeling and Data Analysis in Cellular Biophysics
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cellular biophysics deals with the physical aspects of cell biology. This thesis presents a number of studies where mathematical models and data analysis can increase our understanding of this field.

During recent years development in experimental methods and mathematical modeling have driven the amount of data and complexity in our understanding of cellular biology to a new level. This development has made it possible to describe cellular systems quantitatively where only qualitative descriptions were previously possible. To deal with the complex data and models that arise in this kind of research a combination of tools from physics and cell biology has to be applied; this constitutes a field we call cellular biophysics. The aim of this doctoral thesis is to develop novel approaches in this field. I present eight studies where quantitative modeling and analysis are involved.

The first two studies concern cells interacting with their surrounding environment in the kidney. These cells sense fluid flow and respond with calcium (Ca2+) signals. The interaction between fluid and cells in renal tubular epithelium can be described by biomechanical models. This thesis describes a mathematical model of flow sensing by cilia with focus on the flow frequency response and time delay between the mechanical stress and the Ca2+ signaling response.

Intracellular Ca2+ is kept at a very low level compared to the extracellular environment, while several intracellular compartments have higher Ca2+ concentration than the cytoplasm. This makes Ca2+ an efficient messenger for intra­cellular signaling, the process whereby signals are transduced from an extracellular stimulus to an intracellular activity such as gene expression. An important type of Ca2+ signaling is oscillations in intracellular Ca2+ concentration which occur due to the concerted interplay between different transport mechanisms within a cell. A study in this thesis examines ways to explain these mechanisms in terms of a mathematical model. Another study in the thesis reports that erythropoietin can regulate the water permeability of astrocytes and that it alters the pattern of Ca2+ oscillations in astrocytes. In this thesis the analysis of this Ca2+ signaling is described.

Simulations described in one of the studies show how different geometries can affect the fluorescence recovery and that geometrically constrained reactions can trap diffusing receptors in dendritic spines. When separate time scales are present in a fluorescence revovery after photobleaching (FRAP) experiment the reaction and diffusion components can be studied separately.

Applying single particle tracking methods to the migration trajectories of natural killer cells shows that there is a correlation between the formation of conjugates and transient confinement zones (TCZs) in these trajectories in vitro. TCZs are also present in in vivo experiments where they show strong similarities with the in vitro situation. This approach is a novel concept in data analysis methods for tracking immune cells.

Abstract [sv]

Cellens biologiska fysik behandlar de fysikaliska aspekterna av cellbiologi. Denna avhandling presenterar ett antal studier där matematiska modeller och dataanalys kan öka vår förståelse av detta område.

Under senare år har utvecklingen av experimentella metoder och matematisk modellering drivit mängden data och komplexiteten i vår förståelse av cellbiologi till en ny nivå. Denna utveckling har gjort det möjligt att beskriva cellulära system kvantitativt där endast kvalitativa beskrivningar tidigare var möjliga. För att hantera de komplexa data och modeller som uppstår i denna typ av forskning krävs en kombination av verktyg från fysik och cellbiologi; detta utgör ett område vi kallar cellens biologiska fysik. Syftet med denna avhandling är att utveckla nya metoder inom detta område. Jag presenterar åtta studier där kvantitativ modellering och analys ingår.

De första två studierna behandlar hur celler interagerar med sin omgivning i njurarna. Dessa celler känner av ett vätskeflöde och svarar med kalcium (Ca2+)-signaler. Samspelet mellan vätska och celler i tubulärt njurepitel kan beskrivas med biomekaniska modeller. Denna avhandling beskriver en matematisk modell för flödeskänslighet hos cilier med fokus på flödesfrekvenssvar och tidsfördröjningen mellan den mekaniska påverkan och Ca2+-signaleringssvaret.

Intracellulärt Ca2+ hålls på en mycket låg nivå jämfört med den extracellulära miljön, samtidigt som flera intracellulära delar har högre Ca2+-koncentrationen än cytoplasman. Detta gör Ca2+ till en effektiv bärare för intracellulär signalering, den process där signaler överförs från ett extracellulärt stimuli till en intracellulär händelse, exempelvis genuttryck. En viktig typ av Ca2+-signalering är de oscillationer i intracellulär Ca2+-koncentration som uppstår på grund av det ordnade samspelet mellan olika transportmekanismer i en cell. En studie  i denna avhandling undersöker olika sätt att förklara dessa mekanismer i form av en matematisk modell. En annan studie i avhandlingen rapporterar att erytropoietin kan reglera vattenpermeabilitet av astrocyter och att det ändrar mönstret av Ca2+-oscillationer i astrocyter. I denna avhandling beskrivs analysen av denna Ca2+-signalering.

Simuleringar som beskrivs i en av studierna visar hur olika geometrier kan påverka fluorescensåterhämtning och att geometriskt begränsade reaktioner kan fånga in receptorer in i dendrittaggar. När separata tidsskalor förekommer i ett fluorescence revovery after photobleaching (FRAP)-experiment kan reaktions- och diffusionskomponenter studeras separat.

Tillämpande av single particle tracking-metoder på naturliga mördarceller visar att det finns ett samband mellan bildandet av konjugat och transient confinement zones (TCZs) i dessa trajektorier in vitro. TCZs förekommer också i in vivo-experiment där de visar stora likheter med in vitro-situationen. Denna strategi är ett nytt grepp inom dataanalys-metoder för att spåra immunceller.

Place, publisher, year, edition, pages
Stockholm: KTH, 2009. viii, 72 p.
Series
Trita-FYS, ISSN 0280-316X ; 2009:60
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-11368 (URN)978-91-7415-492-4 (ISBN)
Public defence
2009-11-20, FD5, AlbaNova, Roslagstullsbacken 21, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
QC 20100726Available from: 2009-11-03 Created: 2009-10-30 Last updated: 2010-07-26Bibliographically approved

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Publisher's full textScopushttp://www.pnas.org/cgi/content/abstract/103/3/762

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Brismar, Hjalmar

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