Constitutive phosphodiesterase activity restricts spontaneous beating rate of cardiac pacemaker cells by suppressing local Ca2+ releases
Spontaneous beating of rabbit sinoatrial node cells (SANCs) is controlled by cAMP-mediated, protein kinase A-dependent local subsarcolemmal ryanodine receptor Ca(2+) releases (LCRs). LCRs activated an inward Na(+)/Ca(2+) exchange current that increases the terminal diastolic depolarization rate and,...
Uloženo v:
| Vydáno v: | Circulation research Ročník 102; číslo 7; s. 761 |
|---|---|
| Hlavní autoři: | , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
United States
11.04.2008
|
| Témata: | |
| ISSN: | 1524-4571, 1524-4571 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
| Tagy: |
Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
|
| Abstract | Spontaneous beating of rabbit sinoatrial node cells (SANCs) is controlled by cAMP-mediated, protein kinase A-dependent local subsarcolemmal ryanodine receptor Ca(2+) releases (LCRs). LCRs activated an inward Na(+)/Ca(2+) exchange current that increases the terminal diastolic depolarization rate and, therefore, the spontaneous SANC beating rate. Basal cAMP in SANCs is elevated, suggesting that cAMP degradation by phosphodiesterases (PDEs) may be low. Surprisingly, total suppression of PDE activity with a broad-spectrum PDE inhibitor, 3'-isobutylmethylxanthine (IBMX), produced a 9-fold increase in the cAMP level, doubled cAMP-mediated, protein kinase A-dependent phospholamban phosphorylation, and increased SANC firing rate by approximately 55%, indicating a high basal activity of PDEs in SANCs. A comparison of specific PDE1 to -5 inhibitors revealed that the specific PDE3 inhibitor, milrinone, accelerated spontaneous firing by approximately 47% (effects of others were minor) and increased amplitude of L-type Ca(2+) current (I(Ca,L)) by approximately 46%, indicating that PDE3 was the major constitutively active PDE in the basal state. PDE-dependent control of the spontaneous SANC firing was critically dependent on subsarcolemmal LCRs, ie, PDE inhibition increased LCR amplitude and size and decreased LCR period, leading to earlier and augmented LCR Ca(2+) release, Na(+)/Ca(2+) exchange current, and an increase in the firing rate. When ryanodine receptors were disabled by ryanodine, neither IBMX nor milrinone was able to amplify LCRs, accelerate diastolic depolarization rate, or increase the SANC firing rate, despite preserved PDE inhibition-induced augmentation of I(Ca,L) amplitude. Thus, basal constitutive PDE activation provides a novel and powerful mechanism to decrease cAMP, limit cAMP-mediated, protein kinase A-dependent increase of diastolic ryanodine receptor Ca(2+) release, and restrict the spontaneous SANC beating rate. |
|---|---|
| AbstractList | Spontaneous beating of rabbit sinoatrial node cells (SANCs) is controlled by cAMP-mediated, protein kinase A-dependent local subsarcolemmal ryanodine receptor Ca(2+) releases (LCRs). LCRs activated an inward Na(+)/Ca(2+) exchange current that increases the terminal diastolic depolarization rate and, therefore, the spontaneous SANC beating rate. Basal cAMP in SANCs is elevated, suggesting that cAMP degradation by phosphodiesterases (PDEs) may be low. Surprisingly, total suppression of PDE activity with a broad-spectrum PDE inhibitor, 3'-isobutylmethylxanthine (IBMX), produced a 9-fold increase in the cAMP level, doubled cAMP-mediated, protein kinase A-dependent phospholamban phosphorylation, and increased SANC firing rate by approximately 55%, indicating a high basal activity of PDEs in SANCs. A comparison of specific PDE1 to -5 inhibitors revealed that the specific PDE3 inhibitor, milrinone, accelerated spontaneous firing by approximately 47% (effects of others were minor) and increased amplitude of L-type Ca(2+) current (I(Ca,L)) by approximately 46%, indicating that PDE3 was the major constitutively active PDE in the basal state. PDE-dependent control of the spontaneous SANC firing was critically dependent on subsarcolemmal LCRs, ie, PDE inhibition increased LCR amplitude and size and decreased LCR period, leading to earlier and augmented LCR Ca(2+) release, Na(+)/Ca(2+) exchange current, and an increase in the firing rate. When ryanodine receptors were disabled by ryanodine, neither IBMX nor milrinone was able to amplify LCRs, accelerate diastolic depolarization rate, or increase the SANC firing rate, despite preserved PDE inhibition-induced augmentation of I(Ca,L) amplitude. Thus, basal constitutive PDE activation provides a novel and powerful mechanism to decrease cAMP, limit cAMP-mediated, protein kinase A-dependent increase of diastolic ryanodine receptor Ca(2+) release, and restrict the spontaneous SANC beating rate.Spontaneous beating of rabbit sinoatrial node cells (SANCs) is controlled by cAMP-mediated, protein kinase A-dependent local subsarcolemmal ryanodine receptor Ca(2+) releases (LCRs). LCRs activated an inward Na(+)/Ca(2+) exchange current that increases the terminal diastolic depolarization rate and, therefore, the spontaneous SANC beating rate. Basal cAMP in SANCs is elevated, suggesting that cAMP degradation by phosphodiesterases (PDEs) may be low. Surprisingly, total suppression of PDE activity with a broad-spectrum PDE inhibitor, 3'-isobutylmethylxanthine (IBMX), produced a 9-fold increase in the cAMP level, doubled cAMP-mediated, protein kinase A-dependent phospholamban phosphorylation, and increased SANC firing rate by approximately 55%, indicating a high basal activity of PDEs in SANCs. A comparison of specific PDE1 to -5 inhibitors revealed that the specific PDE3 inhibitor, milrinone, accelerated spontaneous firing by approximately 47% (effects of others were minor) and increased amplitude of L-type Ca(2+) current (I(Ca,L)) by approximately 46%, indicating that PDE3 was the major constitutively active PDE in the basal state. PDE-dependent control of the spontaneous SANC firing was critically dependent on subsarcolemmal LCRs, ie, PDE inhibition increased LCR amplitude and size and decreased LCR period, leading to earlier and augmented LCR Ca(2+) release, Na(+)/Ca(2+) exchange current, and an increase in the firing rate. When ryanodine receptors were disabled by ryanodine, neither IBMX nor milrinone was able to amplify LCRs, accelerate diastolic depolarization rate, or increase the SANC firing rate, despite preserved PDE inhibition-induced augmentation of I(Ca,L) amplitude. Thus, basal constitutive PDE activation provides a novel and powerful mechanism to decrease cAMP, limit cAMP-mediated, protein kinase A-dependent increase of diastolic ryanodine receptor Ca(2+) release, and restrict the spontaneous SANC beating rate. Spontaneous beating of rabbit sinoatrial node cells (SANCs) is controlled by cAMP-mediated, protein kinase A-dependent local subsarcolemmal ryanodine receptor Ca(2+) releases (LCRs). LCRs activated an inward Na(+)/Ca(2+) exchange current that increases the terminal diastolic depolarization rate and, therefore, the spontaneous SANC beating rate. Basal cAMP in SANCs is elevated, suggesting that cAMP degradation by phosphodiesterases (PDEs) may be low. Surprisingly, total suppression of PDE activity with a broad-spectrum PDE inhibitor, 3'-isobutylmethylxanthine (IBMX), produced a 9-fold increase in the cAMP level, doubled cAMP-mediated, protein kinase A-dependent phospholamban phosphorylation, and increased SANC firing rate by approximately 55%, indicating a high basal activity of PDEs in SANCs. A comparison of specific PDE1 to -5 inhibitors revealed that the specific PDE3 inhibitor, milrinone, accelerated spontaneous firing by approximately 47% (effects of others were minor) and increased amplitude of L-type Ca(2+) current (I(Ca,L)) by approximately 46%, indicating that PDE3 was the major constitutively active PDE in the basal state. PDE-dependent control of the spontaneous SANC firing was critically dependent on subsarcolemmal LCRs, ie, PDE inhibition increased LCR amplitude and size and decreased LCR period, leading to earlier and augmented LCR Ca(2+) release, Na(+)/Ca(2+) exchange current, and an increase in the firing rate. When ryanodine receptors were disabled by ryanodine, neither IBMX nor milrinone was able to amplify LCRs, accelerate diastolic depolarization rate, or increase the SANC firing rate, despite preserved PDE inhibition-induced augmentation of I(Ca,L) amplitude. Thus, basal constitutive PDE activation provides a novel and powerful mechanism to decrease cAMP, limit cAMP-mediated, protein kinase A-dependent increase of diastolic ryanodine receptor Ca(2+) release, and restrict the spontaneous SANC beating rate. |
| Author | Ruknudin, Abdul M Vinogradova, Tatiana M Sirenko, Syevda Zhu, Weizhong Lyashkov, Alexey E Li, Yue Younes, Antoine Lakatta, Edward G Spurgeon, Harold Yang, Dongmei |
| Author_xml | – sequence: 1 givenname: Tatiana M surname: Vinogradova fullname: Vinogradova, Tatiana M email: vinogradovat@grc.nia.nih.gov organization: Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224-6825, USA. vinogradovat@grc.nia.nih.gov – sequence: 2 givenname: Syevda surname: Sirenko fullname: Sirenko, Syevda – sequence: 3 givenname: Alexey E surname: Lyashkov fullname: Lyashkov, Alexey E – sequence: 4 givenname: Antoine surname: Younes fullname: Younes, Antoine – sequence: 5 givenname: Yue surname: Li fullname: Li, Yue – sequence: 6 givenname: Weizhong surname: Zhu fullname: Zhu, Weizhong – sequence: 7 givenname: Dongmei surname: Yang fullname: Yang, Dongmei – sequence: 8 givenname: Abdul M surname: Ruknudin fullname: Ruknudin, Abdul M – sequence: 9 givenname: Harold surname: Spurgeon fullname: Spurgeon, Harold – sequence: 10 givenname: Edward G surname: Lakatta fullname: Lakatta, Edward G |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/18276917$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNkNtKxDAQhoMoHlYfQcmVN9I1SQ9pLpeyHmBBWPW6TJOpRrttTVJh38DHNosKXgwz_PPxz-GE7PdDj4ScczbnvODX1f26Wi8fF3eLOWdyHqVCqj1yzHORJVku-f6_-oiceP_GGM9SoQ7JES-FLBSXx-SrGnofbJiC_UQ6vg4-hrHoAzrwSEHHhg1b6qLkrA6e-nHoA_Q4TJ42CMH2L9RBQDq0VIMzFjQdQeMG3tFRjV0XuS310zhGE7_Du0FDRysQV9G3wzjIn5KDFjqPZ795Rp5vlk_VXbJ6uL2vFqvkNRVCJVLJxhgtQBvZgsBUgirLIm0Ek6o1bdkiMKMZy3NhFIBqeKvyTIsSG562hZiRyx_f0Q0fUzyq3li_W_LnolqyTDEleAQvfsGp2aCpR2c34Lb13-_EN_3peMQ |
| ContentType | Journal Article |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1161/CIRCRESAHA.107.161679 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Medicine |
| EISSN | 1524-4571 |
| ExternalDocumentID | 18276917 |
| Genre | Journal Article Research Support, N.I.H., Intramural |
| GrantInformation_xml | – fundername: Intramural NIH HHS |
| GroupedDBID | --- -~X .-D .3C .55 .Z2 01R 0R~ 18M 1J1 29B 2WC 40H 4Q1 4Q2 4Q3 53G 5GY 5RE 5VS 71W 77Y 7O~ AAAAV AAAXR AAGIX AAHPQ AAIQE AAMOA AAMTA AARTV AASOK AAXQO ABBUW ABDIG ABJNI ABOCM ABQRW ABXVJ ABZAD ACCJW ACDDN ACEWG ACGFO ACGFS ACIJW ACILI ACNWC ACPRK ACWDW ACWRI ACXNZ ACZKN ADBBV ADGGA ADHPY ADNKB AE3 AE6 AEETU AENEX AFDTB AFFNX AFUWQ AGINI AHMBA AHOMT AHQNM AHRYX AHVBC AIJEX AINUH AJCLO AJIOK AJNWD AJNYG AJZMW ALKUP ALMA_UNASSIGNED_HOLDINGS AMJPA AMNEI BAWUL BOYCO BQLVK C1A C45 CGR CS3 CUY CVF DIK DIWNM DU5 DUNZO E.X E3Z EBS ECM EIF EJD EX3 F2K F2L F2M F2N F5P FCALG FL- FRP FW0 GX1 H0~ H13 HZ~ H~9 IKREB IKYAY IN~ J5H JK3 JK8 K8S KD2 KMI KQ8 L-C L7B N9A NPM N~7 N~B O9- OAG OAH OB2 OCUKA OK1 OL1 OLG OLH OLU OLV OLY OLZ OPUJH ORVUJ OUVQU OVD OVDNE OVIDH OVLEI OWW OWY OXXIT P2P PQQKQ RAH RLZ S4R S4S T8P TEORI TR2 UPT V2I VVN W3M W8F WH7 WOQ WOW X3V X3W X7M YFH YOC ZFV ZZMQN 7X8 ABPXF ADGHP ADKSD |
| ID | FETCH-LOGICAL-h3229-797bddc2acd7fa2e37a98863b2079fdf8fea0dc00552d9aa9b1f954c28eb13f62 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 90 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000254914300005&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1524-4571 |
| IngestDate | Mon Sep 08 12:27:07 EDT 2025 Thu Apr 03 07:06:43 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 7 |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-h3229-797bddc2acd7fa2e37a98863b2079fdf8fea0dc00552d9aa9b1f954c28eb13f62 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| PMID | 18276917 |
| PQID | 70490921 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_70490921 pubmed_primary_18276917 |
| PublicationCentury | 2000 |
| PublicationDate | 2008-April-11 |
| PublicationDateYYYYMMDD | 2008-04-11 |
| PublicationDate_xml | – month: 04 year: 2008 text: 2008-April-11 day: 11 |
| PublicationDecade | 2000 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Circulation research |
| PublicationTitleAlternate | Circ Res |
| PublicationYear | 2008 |
| SSID | ssj0014329 |
| Score | 2.2384732 |
| Snippet | Spontaneous beating of rabbit sinoatrial node cells (SANCs) is controlled by cAMP-mediated, protein kinase A-dependent local subsarcolemmal ryanodine receptor... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 761 |
| SubjectTerms | 1-Methyl-3-isobutylxanthine - pharmacology Animals Biological Clocks - physiology Calcium - metabolism Calcium-Binding Proteins - metabolism Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Enzyme Activation Heart Rate - physiology Patch-Clamp Techniques Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - drug effects Phosphoric Diester Hydrolases - metabolism Phosphorylation Rabbits Ryanodine Receptor Calcium Release Channel - metabolism Signal Transduction - physiology Sinoatrial Node - metabolism Sinoatrial Node - pathology |
| Title | Constitutive phosphodiesterase activity restricts spontaneous beating rate of cardiac pacemaker cells by suppressing local Ca2+ releases |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/18276917 https://www.proquest.com/docview/70490921 |
| Volume | 102 |
| WOSCitedRecordID | wos000254914300005&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LS8NAEF6qFfHi-1Gfe_AmwSSbZHdBkFIsFWwpotJb2ezDitjUphX8B_5sZ5IUT-LBQ3JKyO5mdh4738xHyLnPUuZbEXmGx9yLdAh60AUCQpUkji03ShSQ_6c73uuJwUD2a-RqUQuDsMqFTiwUtck0npFfckxRyTC4nrx7yBmFudWKQGOJ1Bk4Mgjo4oOfHELECo4yMFCRF8U8qOp3wMW5bN3et2CCzU4Tolc8YcFkxO8-ZmFr2hv_G-UmWa98TNoshWKL1Ox4m6x2qyz6DvlCls4CIgCqjk5GWQ4XogmxGjm3FGsdkFKCIm8H6MlZThFIC26kzeY5TdHNHD9TbDJBM0d1IWSaQvRt39SrnVLMBsBznzSfT0qgLTxeWE3aUuEFRaIW-FC-Sx7bNw-tjlcxMngj2PjS45KnxuhQacOdCi3jSgqRsDT0uXTGCWeVbzQ29gqNVEqmgZMxSIAAk8BcEu6R5XE2tgeEpkz5qUiT2DKDTQsVtsqPnVBM-9zZqEHOFis8BInHgZezHC7WuEH2y580nJSNOYYQK_EE4s_DP989Imsl8CPyguCY1B3sdXtCVvTH7CWfnhaCBPdev_sN1xLV4Q |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Constitutive+phosphodiesterase+activity+restricts+spontaneous+beating+rate+of+cardiac+pacemaker+cells+by+suppressing+local+Ca2%2B+releases&rft.jtitle=Circulation+research&rft.au=Vinogradova%2C+Tatiana+M&rft.au=Sirenko%2C+Syevda&rft.au=Lyashkov%2C+Alexey+E&rft.au=Younes%2C+Antoine&rft.date=2008-04-11&rft.eissn=1524-4571&rft.volume=102&rft.issue=7&rft.spage=761&rft_id=info:doi/10.1161%2FCIRCRESAHA.107.161679&rft_id=info%3Apmid%2F18276917&rft_id=info%3Apmid%2F18276917&rft.externalDocID=18276917 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1524-4571&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1524-4571&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1524-4571&client=summon |