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Experimental and mathematical analysis of cAMP nanodomains
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-170972
- In their role as second messengers, cyclic nucleotides such as cAMP have a variety of intracellular effects. These complex tasks demand a highly organized orchestration of spatially and temporally confined cAMP action which should be best achieved by compartmentalization of the latter. A great body of evidence suggests that cAMP compartments may be established and maintained by cAMP degrading enzymes, e.g. phosphodiesterases (PDEs). However, the molecular and biophysical details of how PDEs can orchestrate cAMP gradients are entirely unclear.In their role as second messengers, cyclic nucleotides such as cAMP have a variety of intracellular effects. These complex tasks demand a highly organized orchestration of spatially and temporally confined cAMP action which should be best achieved by compartmentalization of the latter. A great body of evidence suggests that cAMP compartments may be established and maintained by cAMP degrading enzymes, e.g. phosphodiesterases (PDEs). However, the molecular and biophysical details of how PDEs can orchestrate cAMP gradients are entirely unclear. In this paper, using fusion proteins of cAMP FRET-sensors and PDEs in living cells, we provide direct experimental evidence that the cAMP concentration in the vicinity of an individual PDE molecule is below the detection limit of our FRET sensors (<100nM). This cAMP gradient persists in crude cytosol preparations. We developed mathematical models based on diffusion-reaction equations which describe the creation of nanocompartments around a single PDE molecule and more complex spatial PDE arrangements. The analytically solvable equations derived here explicitly determine how the capability of a single PDE, or PDE complexes, to create a nanocompartment depend on the cAMP degradation rate, the diffusive mobility of cAMP, and geometrical and topological parameters. We apply these generic models to our experimental data and determine the diffusive mobility and degradation rate of cAMP. The results obtained for these parameters differ by far from data in literature for free soluble cAMP interacting with PDE. Hence, restricted cAMP diffusion in the vincinity of PDE is necessary to create cAMP nanocompartments in cells.…
Autor(en): | Christian Lohse, Andreas Bock, Isabella Maiellaro, Annette Hannawacker, Lothar R. Schad, Martin J. Lohse, Wolfgang R. Bauer |
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URN: | urn:nbn:de:bvb:20-opus-170972 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Institut für Pharmakologie und Toxikologie |
Medizinische Fakultät / Medizinische Klinik und Poliklinik I | |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | PLoS ONE |
Erscheinungsjahr: | 2017 |
Band / Jahrgang: | 12 |
Heft / Ausgabe: | 4 |
Seitenangabe: | e0174856 |
Originalveröffentlichung / Quelle: | PLoS ONE 12(4):e0174856 (2017). DOI: 10.1371/journal.pone.0174856 |
DOI: | https://doi.org/10.1371/journal.pone.0174856 |
PubMed-ID: | https://pubmed.ncbi.nlm.nih.gov/28406920 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | absorption; adenylyl cyclase signaling cascade; cell fusion; cyclic nucleotides such as cyclic adenosine monophosphate; cytosol; fluorescence resonance energy transfer; isoproterenol; radii; yellow fluorescent protein |
Datum der Freischaltung: | 14.10.2019 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |