Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism
Abstract Aims Atrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key...
Gespeichert in:
| Veröffentlicht in: | European heart journal 2023-07, Vol.44 (27), p.2483-2494 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2494 |
|---|---|
| container_issue | 27 |
| container_start_page | 2483 |
| container_title | European heart journal |
| container_volume | 44 |
| creator | Grammatika Pavlidou, Nefeli Dobrev, Shokoufeh Beneke, Kira Reinhardt, Franziska Pecha, Simon Jacquet, Eric Abu-Taha, Issam H Schmidt, Constanze Voigt, Niels Kamler, Markus Schnabel, Renate B Baczkó, Istvan Garnier, Anne Reichenspurner, Hermann Nikolaev, Viacheslav O Dobrev, Dobromir Molina, Cristina E |
| description | Abstract
Aims
Atrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key calcium-handling proteins, including the ICa,L-carrying Cav1.2α1C subunit. The aim was to assess whether altered function of PDE type-8 (PDE8) isoforms contributes to the reduction of ICa,L in persistent (chronic) AF (cAF) patients.
Methods and results
mRNA, protein levels, and localization of PDE8A and PDE8B isoforms were measured by RT-qPCR, western blot, co-immunoprecipitation and immunofluorescence. PDE8 function was assessed by FRET, patch-clamp and sharp-electrode recordings. PDE8A gene and protein levels were higher in paroxysmal AF (pAF) vs. sinus rhythm (SR) patients, whereas PDE8B was upregulated in cAF only. Cytosolic abundance of PDE8A was higher in atrial pAF myocytes, whereas PDE8B tended to be more abundant at the plasmalemma in cAF myocytes. In co-immunoprecipitation, only PDE8B2 showed binding to Cav1.2α1C subunit which was strongly increased in cAF. Accordingly, Cav1.2α1C showed a lower phosphorylation at Ser1928 in association with decreased ICa,L in cAF. Selective PDE8 inhibition increased Ser1928 phosphorylation of Cav1.2α1C, enhanced cAMP at the subsarcolemma and rescued the lower ICa,L in cAF, which was accompanied by a prolongation of action potential duration at 50% of repolarization.
Conclusion
Both PDE8A and PDE8B are expressed in human heart. Upregulation of PDE8B isoforms in cAF reduces ICa,L via direct interaction of PDE8B2 with the Cav1.2α1C subunit. Thus, upregulated PDE8B2 might serve as a novel molecular mechanism of the proarrhythmic reduction of ICa,L in cAF.
Structured Graphical Abstract
Structured Graphical Abstract
The reduction of L-type Ca2+-current in atrial myocytes promotes atrial fibrillation. Phosphodiesterase type 8B binds L-type Ca2+ channels and reduces local cAMP levels and PKA-dependent channel phosphorylation, thereby decreasing L-type Ca2+-current and abbreviating atrial action potential that promotes atrial fibrillation persistence. ADP, adenosine diphosphate; cAF, persistent (chronic) atrial fibrillation; cAMP, cyclic adenosine monophosphate; DAD, delayed afterdepolarization; ICa,L, L-type Ca2+ current; LTCC, L-type Ca2+ channel; PDE, phosphodiesterase; PLB, phospholamban; RyR2, ryanodine receptor type 2; S |
| doi_str_mv | 10.1093/eurheartj/ehad086 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10344654</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/eurheartj/ehad086</oup_id><sourcerecordid>2779346528</sourcerecordid><originalsourceid>FETCH-LOGICAL-c471t-79f8d25365f097ec3c183a08f156a99986251a3bbe4663ab4c97393ec4a2fa6b3</originalsourceid><addsrcrecordid>eNqNkUGP1CAYhhujccfVH-DFcNTEOlBaWryYyUZd4xjnoIk38pV-Xdi00IV2k_kZ_mOZzDhRT55I4Hkf4Huz7DmjbxiVfI1LMAhhvl2jgY424kG2YlVR5FKU1cNsRZmsciGaHxfZkxhvKU0IE4-zCy4aRmtZrrKfO-PjZHxnMc4YICJpyI2_x-Ai0Zsvu_Xu8ybvcELXoZtJwG7Rs_WO-J5s83k_IdEwaLuMRC8hHBjriFlGcATmYGEgvW2DHQY4xN4SIC7pBwIhmP1sRn-DzmoyojbgbByfZo96GCI-O62X2fcP779dXefbrx8_XW22uS5rNue17JuuqLioeipr1FyzhgNtelYJkFI2oqgY8LbFUggOballzSVHXULRg2j5Zfbu6J2WdsROp5cHGNQU7AhhrzxY9feJs0alyShGeVmKqkyGV0eD-Sd3vdmqwx4tmWhkze5ZYl-ebgv-bkmzVqONGtNUHPolqqKuJU_WokkoO6I6-BgD9mc3o-rQuzr3rk69p8yLPz9zTvwuOgGvj4Bfpv_w_QIFYb-t</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2779346528</pqid></control><display><type>article</type><title>Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Oxford University Press Journals All Titles (1996-Current)</source><source>Alma/SFX Local Collection</source><creator>Grammatika Pavlidou, Nefeli ; Dobrev, Shokoufeh ; Beneke, Kira ; Reinhardt, Franziska ; Pecha, Simon ; Jacquet, Eric ; Abu-Taha, Issam H ; Schmidt, Constanze ; Voigt, Niels ; Kamler, Markus ; Schnabel, Renate B ; Baczkó, Istvan ; Garnier, Anne ; Reichenspurner, Hermann ; Nikolaev, Viacheslav O ; Dobrev, Dobromir ; Molina, Cristina E</creator><creatorcontrib>Grammatika Pavlidou, Nefeli ; Dobrev, Shokoufeh ; Beneke, Kira ; Reinhardt, Franziska ; Pecha, Simon ; Jacquet, Eric ; Abu-Taha, Issam H ; Schmidt, Constanze ; Voigt, Niels ; Kamler, Markus ; Schnabel, Renate B ; Baczkó, Istvan ; Garnier, Anne ; Reichenspurner, Hermann ; Nikolaev, Viacheslav O ; Dobrev, Dobromir ; Molina, Cristina E</creatorcontrib><description>Abstract
Aims
Atrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key calcium-handling proteins, including the ICa,L-carrying Cav1.2α1C subunit. The aim was to assess whether altered function of PDE type-8 (PDE8) isoforms contributes to the reduction of ICa,L in persistent (chronic) AF (cAF) patients.
Methods and results
mRNA, protein levels, and localization of PDE8A and PDE8B isoforms were measured by RT-qPCR, western blot, co-immunoprecipitation and immunofluorescence. PDE8 function was assessed by FRET, patch-clamp and sharp-electrode recordings. PDE8A gene and protein levels were higher in paroxysmal AF (pAF) vs. sinus rhythm (SR) patients, whereas PDE8B was upregulated in cAF only. Cytosolic abundance of PDE8A was higher in atrial pAF myocytes, whereas PDE8B tended to be more abundant at the plasmalemma in cAF myocytes. In co-immunoprecipitation, only PDE8B2 showed binding to Cav1.2α1C subunit which was strongly increased in cAF. Accordingly, Cav1.2α1C showed a lower phosphorylation at Ser1928 in association with decreased ICa,L in cAF. Selective PDE8 inhibition increased Ser1928 phosphorylation of Cav1.2α1C, enhanced cAMP at the subsarcolemma and rescued the lower ICa,L in cAF, which was accompanied by a prolongation of action potential duration at 50% of repolarization.
Conclusion
Both PDE8A and PDE8B are expressed in human heart. Upregulation of PDE8B isoforms in cAF reduces ICa,L via direct interaction of PDE8B2 with the Cav1.2α1C subunit. Thus, upregulated PDE8B2 might serve as a novel molecular mechanism of the proarrhythmic reduction of ICa,L in cAF.
Structured Graphical Abstract
Structured Graphical Abstract
The reduction of L-type Ca2+-current in atrial myocytes promotes atrial fibrillation. Phosphodiesterase type 8B binds L-type Ca2+ channels and reduces local cAMP levels and PKA-dependent channel phosphorylation, thereby decreasing L-type Ca2+-current and abbreviating atrial action potential that promotes atrial fibrillation persistence. ADP, adenosine diphosphate; cAF, persistent (chronic) atrial fibrillation; cAMP, cyclic adenosine monophosphate; DAD, delayed afterdepolarization; ICa,L, L-type Ca2+ current; LTCC, L-type Ca2+ channel; PDE, phosphodiesterase; PLB, phospholamban; RyR2, ryanodine receptor type 2; SERCA2a, sarcoplasmic reticulum Ca2 + ATPase type 2a; SLN, sarcolipin; SR, sinus rhythm.</description><identifier>ISSN: 0195-668X</identifier><identifier>EISSN: 1522-9645</identifier><identifier>DOI: 10.1093/eurheartj/ehad086</identifier><identifier>PMID: 36810794</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Atrial Fibrillation ; Biochemistry ; Biochemistry, Molecular Biology ; Calcium - metabolism ; Cardiology and cardiovascular system ; Genomics ; Human health and pathology ; Humans ; Life Sciences ; Myocytes, Cardiac - physiology ; Phosphoric Diester Hydrolases - metabolism ; Phosphorylation ; Translational Research</subject><ispartof>European heart journal, 2023-07, Vol.44 (27), p.2483-2494</ispartof><rights>The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. 2023</rights><rights>The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-79f8d25365f097ec3c183a08f156a99986251a3bbe4663ab4c97393ec4a2fa6b3</citedby><cites>FETCH-LOGICAL-c471t-79f8d25365f097ec3c183a08f156a99986251a3bbe4663ab4c97393ec4a2fa6b3</cites><orcidid>0000-0002-9588-0797 ; 0000-0001-6608-8496 ; 0000-0001-8230-2341 ; 0000-0002-4612-117X ; 0000-0002-8747-166X ; 0000-0003-3094-1568 ; 0000-0002-7529-5179 ; 0000-0001-6366-8436 ; 0000-0001-5897-237X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,1585,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36810794$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04168971$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Grammatika Pavlidou, Nefeli</creatorcontrib><creatorcontrib>Dobrev, Shokoufeh</creatorcontrib><creatorcontrib>Beneke, Kira</creatorcontrib><creatorcontrib>Reinhardt, Franziska</creatorcontrib><creatorcontrib>Pecha, Simon</creatorcontrib><creatorcontrib>Jacquet, Eric</creatorcontrib><creatorcontrib>Abu-Taha, Issam H</creatorcontrib><creatorcontrib>Schmidt, Constanze</creatorcontrib><creatorcontrib>Voigt, Niels</creatorcontrib><creatorcontrib>Kamler, Markus</creatorcontrib><creatorcontrib>Schnabel, Renate B</creatorcontrib><creatorcontrib>Baczkó, Istvan</creatorcontrib><creatorcontrib>Garnier, Anne</creatorcontrib><creatorcontrib>Reichenspurner, Hermann</creatorcontrib><creatorcontrib>Nikolaev, Viacheslav O</creatorcontrib><creatorcontrib>Dobrev, Dobromir</creatorcontrib><creatorcontrib>Molina, Cristina E</creatorcontrib><title>Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism</title><title>European heart journal</title><addtitle>Eur Heart J</addtitle><description>Abstract
Aims
Atrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key calcium-handling proteins, including the ICa,L-carrying Cav1.2α1C subunit. The aim was to assess whether altered function of PDE type-8 (PDE8) isoforms contributes to the reduction of ICa,L in persistent (chronic) AF (cAF) patients.
Methods and results
mRNA, protein levels, and localization of PDE8A and PDE8B isoforms were measured by RT-qPCR, western blot, co-immunoprecipitation and immunofluorescence. PDE8 function was assessed by FRET, patch-clamp and sharp-electrode recordings. PDE8A gene and protein levels were higher in paroxysmal AF (pAF) vs. sinus rhythm (SR) patients, whereas PDE8B was upregulated in cAF only. Cytosolic abundance of PDE8A was higher in atrial pAF myocytes, whereas PDE8B tended to be more abundant at the plasmalemma in cAF myocytes. In co-immunoprecipitation, only PDE8B2 showed binding to Cav1.2α1C subunit which was strongly increased in cAF. Accordingly, Cav1.2α1C showed a lower phosphorylation at Ser1928 in association with decreased ICa,L in cAF. Selective PDE8 inhibition increased Ser1928 phosphorylation of Cav1.2α1C, enhanced cAMP at the subsarcolemma and rescued the lower ICa,L in cAF, which was accompanied by a prolongation of action potential duration at 50% of repolarization.
Conclusion
Both PDE8A and PDE8B are expressed in human heart. Upregulation of PDE8B isoforms in cAF reduces ICa,L via direct interaction of PDE8B2 with the Cav1.2α1C subunit. Thus, upregulated PDE8B2 might serve as a novel molecular mechanism of the proarrhythmic reduction of ICa,L in cAF.
Structured Graphical Abstract
Structured Graphical Abstract
The reduction of L-type Ca2+-current in atrial myocytes promotes atrial fibrillation. Phosphodiesterase type 8B binds L-type Ca2+ channels and reduces local cAMP levels and PKA-dependent channel phosphorylation, thereby decreasing L-type Ca2+-current and abbreviating atrial action potential that promotes atrial fibrillation persistence. ADP, adenosine diphosphate; cAF, persistent (chronic) atrial fibrillation; cAMP, cyclic adenosine monophosphate; DAD, delayed afterdepolarization; ICa,L, L-type Ca2+ current; LTCC, L-type Ca2+ channel; PDE, phosphodiesterase; PLB, phospholamban; RyR2, ryanodine receptor type 2; SERCA2a, sarcoplasmic reticulum Ca2 + ATPase type 2a; SLN, sarcolipin; SR, sinus rhythm.</description><subject>Atrial Fibrillation</subject><subject>Biochemistry</subject><subject>Biochemistry, Molecular Biology</subject><subject>Calcium - metabolism</subject><subject>Cardiology and cardiovascular system</subject><subject>Genomics</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Myocytes, Cardiac - physiology</subject><subject>Phosphoric Diester Hydrolases - metabolism</subject><subject>Phosphorylation</subject><subject>Translational Research</subject><issn>0195-668X</issn><issn>1522-9645</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNqNkUGP1CAYhhujccfVH-DFcNTEOlBaWryYyUZd4xjnoIk38pV-Xdi00IV2k_kZ_mOZzDhRT55I4Hkf4Huz7DmjbxiVfI1LMAhhvl2jgY424kG2YlVR5FKU1cNsRZmsciGaHxfZkxhvKU0IE4-zCy4aRmtZrrKfO-PjZHxnMc4YICJpyI2_x-Ai0Zsvu_Xu8ybvcELXoZtJwG7Rs_WO-J5s83k_IdEwaLuMRC8hHBjriFlGcATmYGEgvW2DHQY4xN4SIC7pBwIhmP1sRn-DzmoyojbgbByfZo96GCI-O62X2fcP779dXefbrx8_XW22uS5rNue17JuuqLioeipr1FyzhgNtelYJkFI2oqgY8LbFUggOballzSVHXULRg2j5Zfbu6J2WdsROp5cHGNQU7AhhrzxY9feJs0alyShGeVmKqkyGV0eD-Sd3vdmqwx4tmWhkze5ZYl-ebgv-bkmzVqONGtNUHPolqqKuJU_WokkoO6I6-BgD9mc3o-rQuzr3rk69p8yLPz9zTvwuOgGvj4Bfpv_w_QIFYb-t</recordid><startdate>20230714</startdate><enddate>20230714</enddate><creator>Grammatika Pavlidou, Nefeli</creator><creator>Dobrev, Shokoufeh</creator><creator>Beneke, Kira</creator><creator>Reinhardt, Franziska</creator><creator>Pecha, Simon</creator><creator>Jacquet, Eric</creator><creator>Abu-Taha, Issam H</creator><creator>Schmidt, Constanze</creator><creator>Voigt, Niels</creator><creator>Kamler, Markus</creator><creator>Schnabel, Renate B</creator><creator>Baczkó, Istvan</creator><creator>Garnier, Anne</creator><creator>Reichenspurner, Hermann</creator><creator>Nikolaev, Viacheslav O</creator><creator>Dobrev, Dobromir</creator><creator>Molina, Cristina E</creator><general>Oxford University Press</general><general>Oxford University Press (OUP)</general><scope>TOX</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>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9588-0797</orcidid><orcidid>https://orcid.org/0000-0001-6608-8496</orcidid><orcidid>https://orcid.org/0000-0001-8230-2341</orcidid><orcidid>https://orcid.org/0000-0002-4612-117X</orcidid><orcidid>https://orcid.org/0000-0002-8747-166X</orcidid><orcidid>https://orcid.org/0000-0003-3094-1568</orcidid><orcidid>https://orcid.org/0000-0002-7529-5179</orcidid><orcidid>https://orcid.org/0000-0001-6366-8436</orcidid><orcidid>https://orcid.org/0000-0001-5897-237X</orcidid></search><sort><creationdate>20230714</creationdate><title>Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism</title><author>Grammatika Pavlidou, Nefeli ; Dobrev, Shokoufeh ; Beneke, Kira ; Reinhardt, Franziska ; Pecha, Simon ; Jacquet, Eric ; Abu-Taha, Issam H ; Schmidt, Constanze ; Voigt, Niels ; Kamler, Markus ; Schnabel, Renate B ; Baczkó, Istvan ; Garnier, Anne ; Reichenspurner, Hermann ; Nikolaev, Viacheslav O ; Dobrev, Dobromir ; Molina, Cristina E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c471t-79f8d25365f097ec3c183a08f156a99986251a3bbe4663ab4c97393ec4a2fa6b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Atrial Fibrillation</topic><topic>Biochemistry</topic><topic>Biochemistry, Molecular Biology</topic><topic>Calcium - metabolism</topic><topic>Cardiology and cardiovascular system</topic><topic>Genomics</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Myocytes, Cardiac - physiology</topic><topic>Phosphoric Diester Hydrolases - metabolism</topic><topic>Phosphorylation</topic><topic>Translational Research</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grammatika Pavlidou, Nefeli</creatorcontrib><creatorcontrib>Dobrev, Shokoufeh</creatorcontrib><creatorcontrib>Beneke, Kira</creatorcontrib><creatorcontrib>Reinhardt, Franziska</creatorcontrib><creatorcontrib>Pecha, Simon</creatorcontrib><creatorcontrib>Jacquet, Eric</creatorcontrib><creatorcontrib>Abu-Taha, Issam H</creatorcontrib><creatorcontrib>Schmidt, Constanze</creatorcontrib><creatorcontrib>Voigt, Niels</creatorcontrib><creatorcontrib>Kamler, Markus</creatorcontrib><creatorcontrib>Schnabel, Renate B</creatorcontrib><creatorcontrib>Baczkó, Istvan</creatorcontrib><creatorcontrib>Garnier, Anne</creatorcontrib><creatorcontrib>Reichenspurner, Hermann</creatorcontrib><creatorcontrib>Nikolaev, Viacheslav O</creatorcontrib><creatorcontrib>Dobrev, Dobromir</creatorcontrib><creatorcontrib>Molina, Cristina E</creatorcontrib><collection>Access via Oxford University Press (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European heart journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grammatika Pavlidou, Nefeli</au><au>Dobrev, Shokoufeh</au><au>Beneke, Kira</au><au>Reinhardt, Franziska</au><au>Pecha, Simon</au><au>Jacquet, Eric</au><au>Abu-Taha, Issam H</au><au>Schmidt, Constanze</au><au>Voigt, Niels</au><au>Kamler, Markus</au><au>Schnabel, Renate B</au><au>Baczkó, Istvan</au><au>Garnier, Anne</au><au>Reichenspurner, Hermann</au><au>Nikolaev, Viacheslav O</au><au>Dobrev, Dobromir</au><au>Molina, Cristina E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism</atitle><jtitle>European heart journal</jtitle><addtitle>Eur Heart J</addtitle><date>2023-07-14</date><risdate>2023</risdate><volume>44</volume><issue>27</issue><spage>2483</spage><epage>2494</epage><pages>2483-2494</pages><issn>0195-668X</issn><eissn>1522-9645</eissn><abstract>Abstract
Aims
Atrial fibrillation (AF) is associated with altered cAMP/PKA signaling and an AF-promoting reduction of L-type Ca2+-current (ICa,L), the mechanisms of which are poorly understood. Cyclic-nucleotide phosphodiesterases (PDEs) degrade cAMP and regulate PKA-dependent phosphorylation of key calcium-handling proteins, including the ICa,L-carrying Cav1.2α1C subunit. The aim was to assess whether altered function of PDE type-8 (PDE8) isoforms contributes to the reduction of ICa,L in persistent (chronic) AF (cAF) patients.
Methods and results
mRNA, protein levels, and localization of PDE8A and PDE8B isoforms were measured by RT-qPCR, western blot, co-immunoprecipitation and immunofluorescence. PDE8 function was assessed by FRET, patch-clamp and sharp-electrode recordings. PDE8A gene and protein levels were higher in paroxysmal AF (pAF) vs. sinus rhythm (SR) patients, whereas PDE8B was upregulated in cAF only. Cytosolic abundance of PDE8A was higher in atrial pAF myocytes, whereas PDE8B tended to be more abundant at the plasmalemma in cAF myocytes. In co-immunoprecipitation, only PDE8B2 showed binding to Cav1.2α1C subunit which was strongly increased in cAF. Accordingly, Cav1.2α1C showed a lower phosphorylation at Ser1928 in association with decreased ICa,L in cAF. Selective PDE8 inhibition increased Ser1928 phosphorylation of Cav1.2α1C, enhanced cAMP at the subsarcolemma and rescued the lower ICa,L in cAF, which was accompanied by a prolongation of action potential duration at 50% of repolarization.
Conclusion
Both PDE8A and PDE8B are expressed in human heart. Upregulation of PDE8B isoforms in cAF reduces ICa,L via direct interaction of PDE8B2 with the Cav1.2α1C subunit. Thus, upregulated PDE8B2 might serve as a novel molecular mechanism of the proarrhythmic reduction of ICa,L in cAF.
Structured Graphical Abstract
Structured Graphical Abstract
The reduction of L-type Ca2+-current in atrial myocytes promotes atrial fibrillation. Phosphodiesterase type 8B binds L-type Ca2+ channels and reduces local cAMP levels and PKA-dependent channel phosphorylation, thereby decreasing L-type Ca2+-current and abbreviating atrial action potential that promotes atrial fibrillation persistence. ADP, adenosine diphosphate; cAF, persistent (chronic) atrial fibrillation; cAMP, cyclic adenosine monophosphate; DAD, delayed afterdepolarization; ICa,L, L-type Ca2+ current; LTCC, L-type Ca2+ channel; PDE, phosphodiesterase; PLB, phospholamban; RyR2, ryanodine receptor type 2; SERCA2a, sarcoplasmic reticulum Ca2 + ATPase type 2a; SLN, sarcolipin; SR, sinus rhythm.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>36810794</pmid><doi>10.1093/eurheartj/ehad086</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-9588-0797</orcidid><orcidid>https://orcid.org/0000-0001-6608-8496</orcidid><orcidid>https://orcid.org/0000-0001-8230-2341</orcidid><orcidid>https://orcid.org/0000-0002-4612-117X</orcidid><orcidid>https://orcid.org/0000-0002-8747-166X</orcidid><orcidid>https://orcid.org/0000-0003-3094-1568</orcidid><orcidid>https://orcid.org/0000-0002-7529-5179</orcidid><orcidid>https://orcid.org/0000-0001-6366-8436</orcidid><orcidid>https://orcid.org/0000-0001-5897-237X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0195-668X |
| ispartof | European heart journal, 2023-07, Vol.44 (27), p.2483-2494 |
| issn | 0195-668X 1522-9645 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10344654 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Atrial Fibrillation Biochemistry Biochemistry, Molecular Biology Calcium - metabolism Cardiology and cardiovascular system Genomics Human health and pathology Humans Life Sciences Myocytes, Cardiac - physiology Phosphoric Diester Hydrolases - metabolism Phosphorylation Translational Research |
| title | Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-14T13%3A50%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phosphodiesterase%208%20governs%20cAMP/PKA-dependent%20reduction%20of%20L-type%20calcium%20current%20in%20human%20atrial%20fibrillation:%20a%20novel%20arrhythmogenic%20mechanism&rft.jtitle=European%20heart%20journal&rft.au=Grammatika%20Pavlidou,%20Nefeli&rft.date=2023-07-14&rft.volume=44&rft.issue=27&rft.spage=2483&rft.epage=2494&rft.pages=2483-2494&rft.issn=0195-668X&rft.eissn=1522-9645&rft_id=info:doi/10.1093/eurheartj/ehad086&rft_dat=%3Cproquest_pubme%3E2779346528%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2779346528&rft_id=info:pmid/36810794&rft_oup_id=10.1093/eurheartj/ehad086&rfr_iscdi=true |