Experimental and mathematical analysis of cAMP nanodomains
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...
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| description | 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 ( |
| doi_str_mv | 10.1371/journal.pone.0174856 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0174856</identifier><identifier>PMID: 28406920</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Biology and Life Sciences ; Camps ; Cell Line ; Cells (biology) ; Clinical medicine ; Compartments ; Cyclic adenosine monophosphate ; Cyclic AMP ; Cyclic AMP - metabolism ; Cyclic nucleotides ; Cytosol ; Cytosol - metabolism ; Degradation ; Diffusion ; Enzymes ; Fluorescence resonance energy transfer ; Fretting ; Heart failure ; Humans ; Interdisciplinary aspects ; Kinases ; Mathematical models ; Medicine ; Medicine and Health Sciences ; Mobility ; Models, Biological ; Nanostructure ; Nucleotides ; Numerical analysis ; Pharmacology ; Phosphoric Diester Hydrolases - metabolism ; Physical Sciences ; Physiological aspects ; Proteins ; Reaction-diffusion equations ; Research and Analysis Methods ; Second messengers ; Sensors ; Structure ; Studies ; Task complexity ; Toxicology</subject><ispartof>PloS one, 2017-04, Vol.12 (4), p.e0174856</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Lohse et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Lohse et al 2017 Lohse et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-19e40becf7c8bd014d3b1f0f453981696b512970d4636d6d645ecb522ea42c523</citedby><cites>FETCH-LOGICAL-c692t-19e40becf7c8bd014d3b1f0f453981696b512970d4636d6d645ecb522ea42c523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391016/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391016/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28406920$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Tasken, Kjetil</contributor><creatorcontrib>Lohse, Christian</creatorcontrib><creatorcontrib>Bock, Andreas</creatorcontrib><creatorcontrib>Maiellaro, Isabella</creatorcontrib><creatorcontrib>Hannawacker, Annette</creatorcontrib><creatorcontrib>Schad, Lothar R</creatorcontrib><creatorcontrib>Lohse, Martin J</creatorcontrib><creatorcontrib>Bauer, Wolfgang R</creatorcontrib><title>Experimental and mathematical analysis of cAMP nanodomains</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>In their role as second messengers, cyclic nucleotides such as cAMP have a variety of intracellular effects. 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Hence, restricted cAMP diffusion in the vincinity of PDE is necessary to create cAMP nanocompartments in cells.</description><subject>Biology and Life Sciences</subject><subject>Camps</subject><subject>Cell Line</subject><subject>Cells (biology)</subject><subject>Clinical medicine</subject><subject>Compartments</subject><subject>Cyclic adenosine monophosphate</subject><subject>Cyclic AMP</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic nucleotides</subject><subject>Cytosol</subject><subject>Cytosol - metabolism</subject><subject>Degradation</subject><subject>Diffusion</subject><subject>Enzymes</subject><subject>Fluorescence resonance energy transfer</subject><subject>Fretting</subject><subject>Heart failure</subject><subject>Humans</subject><subject>Interdisciplinary aspects</subject><subject>Kinases</subject><subject>Mathematical models</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mobility</subject><subject>Models, Biological</subject><subject>Nanostructure</subject><subject>Nucleotides</subject><subject>Numerical analysis</subject><subject>Pharmacology</subject><subject>Phosphoric Diester Hydrolases - metabolism</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Reaction-diffusion equations</subject><subject>Research and Analysis Methods</subject><subject>Second messengers</subject><subject>Sensors</subject><subject>Structure</subject><subject>Studies</subject><subject>Task complexity</subject><subject>Toxicology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1rFDEUhgdRbK3-A9EFoeDFrvmejBfCUqouVCp-3YYzmcxulplkncyU9t972p2WHVCQQBJOnvdNzsnJspeULCjP6bttHLoAzWIXg1sQmgst1aPsmBaczRUj_PHB_ih7ltKWEMm1Uk-zI6YFUQUjx9n78-ud63zrQg_NDEI1a6HfOJy8vQtAc5N8msV6Zpdfvs4ChFjFFnxIz7MnNTTJvRjXk-znx_MfZ5_nF5efVmfLi7nFK_o5LZwgpbN1bnVZESoqXtKa1ELyQlNVqFJSVuSkEoqrCoeQzpaSMQeCWcn4SfZ677trYjJj2slQrXOOci6RWO2JKsLW7DAd6G5MBG_uArFbG-gwocaZorZaSSlKzbjItSyBUU0LUFA6UjtArw_jbUPZuspiYTpoJqbTk-A3Zh2vDKZDCVVo8GY06OLvwaX-H08eqTXgq3yoI5rZ1idrlkIXkiIlkFr8hcJRudZb_PjaY3wieDsRINO7634NQ0pm9f3b_7OXv6bs6QG7cdD0mxSbofcxpCko9qDtYkqdqx8qR4m57dv7apjbvjVj36Ls1WHVH0T3jcr_AJDs5uo</recordid><startdate>20170413</startdate><enddate>20170413</enddate><creator>Lohse, Christian</creator><creator>Bock, Andreas</creator><creator>Maiellaro, Isabella</creator><creator>Hannawacker, Annette</creator><creator>Schad, Lothar R</creator><creator>Lohse, Martin J</creator><creator>Bauer, Wolfgang R</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20170413</creationdate><title>Experimental and mathematical analysis of cAMP nanodomains</title><author>Lohse, Christian ; Bock, Andreas ; Maiellaro, Isabella ; Hannawacker, Annette ; Schad, Lothar R ; Lohse, Martin J ; Bauer, Wolfgang R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-19e40becf7c8bd014d3b1f0f453981696b512970d4636d6d645ecb522ea42c523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Biology and Life Sciences</topic><topic>Camps</topic><topic>Cell Line</topic><topic>Cells (biology)</topic><topic>Clinical medicine</topic><topic>Compartments</topic><topic>Cyclic adenosine monophosphate</topic><topic>Cyclic AMP</topic><topic>Cyclic AMP - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28406920</pmid><doi>10.1371/journal.pone.0174856</doi><tpages>e0174856</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Biology and Life Sciences Camps Cell Line Cells (biology) Clinical medicine Compartments Cyclic adenosine monophosphate Cyclic AMP Cyclic AMP - metabolism Cyclic nucleotides Cytosol Cytosol - metabolism Degradation Diffusion Enzymes Fluorescence resonance energy transfer Fretting Heart failure Humans Interdisciplinary aspects Kinases Mathematical models Medicine Medicine and Health Sciences Mobility Models, Biological Nanostructure Nucleotides Numerical analysis Pharmacology Phosphoric Diester Hydrolases - metabolism Physical Sciences Physiological aspects Proteins Reaction-diffusion equations Research and Analysis Methods Second messengers Sensors Structure Studies Task complexity Toxicology |
| title | Experimental and mathematical analysis of cAMP nanodomains |
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