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Optogenetic versus Electrical Stimulation of Human Cardiomyocytes: Modeling Insights
Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage, and trigger or modify action potentials (APs) in excitable cells. We compare biophysically and energetically the cellular responses to direct electrical current injection versus optical stimulation mediate...
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Published in: | Biophysical journal 2015-04, Vol.108 (8), p.1934-1945 |
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container_title | Biophysical journal |
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description | Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage, and trigger or modify action potentials (APs) in excitable cells. We compare biophysically and energetically the cellular responses to direct electrical current injection versus optical stimulation mediated by genetically expressed light-sensitive ion channels, e.g., Channelrhodopsin-2 (ChR2). Using a computational model of ChR2(H134R mutant), we show that both stimulation modalities produce similar-in-morphology APs in human cardiomyocytes, and that electrical and optical excitability vary with cell type in a similar fashion. However, whereas the strength-duration curves for electrical excitation in ventricular and atrial cardiomyocytes closely follow the theoretical exponential relationship for an equivalent RC circuit, the respective optical strength-duration curves significantly deviate, exhibiting higher nonlinearity. We trace the origin of this deviation to the waveform of the excitatory current—a nonrectangular self-terminating inward current produced in optical stimulation due to ChR2 kinetics and voltage-dependent rectification. Using a unifying charge measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter APs). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of AP duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation is not feasible due to electrochemical limitations. Our analysis offers insights for designing future new energy-efficient stimulation strategies in heart or brain. |
doi_str_mv | 10.1016/j.bpj.2015.03.032 |
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Using a unifying charge measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter APs). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of AP duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation is not feasible due to electrochemical limitations. 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All rights reserved.</rights><rights>Copyright Biophysical Society Apr 21, 2015</rights><rights>2015 by the Biophysical Society. 2015 Biophysical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c545t-17173873b99556530e9ff639033e23bf7da99faaa242cc5a6fdabbca341510243</citedby><cites>FETCH-LOGICAL-c545t-17173873b99556530e9ff639033e23bf7da99faaa242cc5a6fdabbca341510243</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/PMC4407252/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407252/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25902433$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Williams, John C.</creatorcontrib><creatorcontrib>Entcheva, Emilia</creatorcontrib><title>Optogenetic versus Electrical Stimulation of Human Cardiomyocytes: Modeling Insights</title><title>Biophysical journal</title><addtitle>Biophys J</addtitle><description>Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage, and trigger or modify action potentials (APs) in excitable cells. We compare biophysically and energetically the cellular responses to direct electrical current injection versus optical stimulation mediated by genetically expressed light-sensitive ion channels, e.g., Channelrhodopsin-2 (ChR2). Using a computational model of ChR2(H134R mutant), we show that both stimulation modalities produce similar-in-morphology APs in human cardiomyocytes, and that electrical and optical excitability vary with cell type in a similar fashion. However, whereas the strength-duration curves for electrical excitation in ventricular and atrial cardiomyocytes closely follow the theoretical exponential relationship for an equivalent RC circuit, the respective optical strength-duration curves significantly deviate, exhibiting higher nonlinearity. We trace the origin of this deviation to the waveform of the excitatory current—a nonrectangular self-terminating inward current produced in optical stimulation due to ChR2 kinetics and voltage-dependent rectification. Using a unifying charge measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter APs). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of AP duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation is not feasible due to electrochemical limitations. Our analysis offers insights for designing future new energy-efficient stimulation strategies in heart or brain.</description><subject>Action Potentials</subject><subject>Cardiomyocytes</subject><subject>Cells</subject><subject>Channelrhodopsins</subject><subject>Channels and Transporters</subject><subject>Electric Stimulation - methods</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Models, Cardiovascular</subject><subject>Morphology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - physiology</subject><subject>Optogenetics - methods</subject><subject>Purkinje Fibers - metabolism</subject><subject>Purkinje Fibers - physiology</subject><issn>0006-3495</issn><issn>1542-0086</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNp9kUFrFDEYhoModq3-AC8y4MXLrF-SSWZHQZCltoVKD9ZzyGS-2WaYSdYks7D_3gzbFvUgfJBDnjy8X15C3lJYU6Dy47Bu98OaARVr4HnYM7KiomIlwEY-JysAkCWvGnFGXsU4AFAmgL4kZ0w0wCrOV-Tudp_8Dh0ma4oDhjjH4mJEk4I1eix-JDvNo07Wu8L3xdU8aVdsdeisn47eHBPGT8V33-Fo3a64dtHu7lN8TV70eoz45uE8Jz-_Xdxtr8qb28vr7deb0ohKpJLWtOabmrdNI4QUHLDpe8kb4BwZb_u6003Ta61ZxYwRWvadblujeUUFXfKfky8n735uJ-wMuhT0qPbBTjoclddW_X3j7L3a-YOqKqiZYFnw4UEQ_K8ZY1KTjQbHUTv0c1RU1mJTSylERt__gw5-Di6vt1CyzspNkyl6okzwMQbsn8JQUEtnalC5M7V0poDnWUK8-3OLpxePJWXg8wnA_JcHi0FFY9EZ7GzITanO2__ofwODwKgl</recordid><startdate>20150421</startdate><enddate>20150421</enddate><creator>Williams, John C.</creator><creator>Entcheva, Emilia</creator><general>Elsevier Inc</general><general>Biophysical Society</general><general>The Biophysical Society</general><scope>6I.</scope><scope>AAFTH</scope><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>7QO</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150421</creationdate><title>Optogenetic versus Electrical Stimulation of Human Cardiomyocytes: Modeling Insights</title><author>Williams, John C. ; Entcheva, Emilia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c545t-17173873b99556530e9ff639033e23bf7da99faaa242cc5a6fdabbca341510243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Action Potentials</topic><topic>Cardiomyocytes</topic><topic>Cells</topic><topic>Channelrhodopsins</topic><topic>Channels and Transporters</topic><topic>Electric Stimulation - methods</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Models, Cardiovascular</topic><topic>Morphology</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - physiology</topic><topic>Optogenetics - methods</topic><topic>Purkinje Fibers - metabolism</topic><topic>Purkinje Fibers - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Williams, John C.</creatorcontrib><creatorcontrib>Entcheva, Emilia</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biophysical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Williams, John C.</au><au>Entcheva, Emilia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optogenetic versus Electrical Stimulation of Human Cardiomyocytes: Modeling Insights</atitle><jtitle>Biophysical journal</jtitle><addtitle>Biophys J</addtitle><date>2015-04-21</date><risdate>2015</risdate><volume>108</volume><issue>8</issue><spage>1934</spage><epage>1945</epage><pages>1934-1945</pages><issn>0006-3495</issn><eissn>1542-0086</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage, and trigger or modify action potentials (APs) in excitable cells. We compare biophysically and energetically the cellular responses to direct electrical current injection versus optical stimulation mediated by genetically expressed light-sensitive ion channels, e.g., Channelrhodopsin-2 (ChR2). Using a computational model of ChR2(H134R mutant), we show that both stimulation modalities produce similar-in-morphology APs in human cardiomyocytes, and that electrical and optical excitability vary with cell type in a similar fashion. However, whereas the strength-duration curves for electrical excitation in ventricular and atrial cardiomyocytes closely follow the theoretical exponential relationship for an equivalent RC circuit, the respective optical strength-duration curves significantly deviate, exhibiting higher nonlinearity. We trace the origin of this deviation to the waveform of the excitatory current—a nonrectangular self-terminating inward current produced in optical stimulation due to ChR2 kinetics and voltage-dependent rectification. Using a unifying charge measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter APs). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of AP duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation is not feasible due to electrochemical limitations. 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subjects | Action Potentials Cardiomyocytes Cells Channelrhodopsins Channels and Transporters Electric Stimulation - methods Gene expression Humans Kinetics Models, Cardiovascular Morphology Myocytes, Cardiac - metabolism Myocytes, Cardiac - physiology Optogenetics - methods Purkinje Fibers - metabolism Purkinje Fibers - physiology |
title | Optogenetic versus Electrical Stimulation of Human Cardiomyocytes: Modeling Insights |
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