{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:31:55Z","timestamp":1790487115345,"version":"4.1.0"},"reference-count":70,"publisher":"Rockefeller University Press","issue":"2","license":[{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"content-version":"vor","delay-in-days":987,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2017,8,7]],"date-time":"2017-08-07T00:00:00Z","timestamp":1502064000000},"content-version":"vor","delay-in-days":214,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01-HL088427"],"award-info":[{"award-number":["R01-HL088427"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["5T32-AG000279"],"award-info":[{"award-number":["5T32-AG000279"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["F31 HL132408"],"award-info":[{"award-number":["F31 HL132408"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,2,1]]},"abstract":"<jats:p>Aerobic capacity decreases with age, in part because of an age-dependent decline in maximum heart rate (mHR) and a reduction in the intrinsic pacemaker activity of the sinoatrial node of the heart. Isolated sinoatrial node myocytes (SAMs) from aged mice have slower spontaneous action potential (AP) firing rates and a hyperpolarizing shift in the voltage dependence of activation of the \u201cfunny current,\u201d If. Cyclic AMP (cAMP)\u00a0is a critical modulator of both\u00a0AP firing rate and If\u00a0in SAMs.\u00a0Here,\u00a0we test\u00a0the ability of endogenous and exogenous cAMP to overcome age-dependent changes in acutely isolated murine SAMs. We found that maximal stimulation of endogenous cAMP with 3-isobutyl-1-methylxanthine (IBMX) and forskolin significantly increased AP firing rate and depolarized the voltage dependence of activation of If in SAMs from both young and aged mice. However, these changes were insufficient to overcome the deficits in aged SAMs, and significant age-dependent differences in AP firing rate and If persisted in the presence of IBMX and forskolin. In contrast, the effects of aging on SAMs were completely abolished by a high concentration of exogenous cAMP, which restored AP firing rate and If activation to youthful levels in cells from aged animals. Interestingly, the age-dependent differences in AP firing rates and If were similar in whole-cell and perforated-patch recordings, and the hyperpolarizing shift in If persisted in excised inside-out patches, suggesting a limited role for cAMP in causing these changes. Collectively, the data indicate that aging does not impose an absolute limit on pacemaker activity and that it does not act by simply reducing the concentration of freely diffusible cAMP in SAMs.<\/jats:p>","DOI":"10.1085\/jgp.201611674","type":"journal-article","created":{"date-parts":[[2017,1,20]],"date-time":"2017-01-20T14:57:22Z","timestamp":1484924242000},"page":"237-247","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Cyclic AMP reverses the effects of aging on pacemaker activity and If in sinoatrial node myocytes"],"prefix":"10.1085","volume":"149","author":[{"given":"Emily J.","family":"Sharpe","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado\u2013Anschutz Medical Campus, Aurora, CO 80045 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2881-4861","authenticated-orcid":true,"given":"Eric D.","family":"Larson","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado\u2013Anschutz Medical Campus, Aurora, CO 80045 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4324-6206","authenticated-orcid":true,"given":"Catherine","family":"Proenza","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado\u2013Anschutz Medical Campus, Aurora, CO 80045 1"},{"name":"Department of Medicine, Division of Cardiology, University of Colorado\u2013Anschutz Medical Campus, Aurora, CO 80045 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,1,5]]},"reference":[{"key":"2023072623574988700_bib1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1111\/j.1540-8167.2011.02140.x","article-title":"Atrial fibrosis quantified using late gadolinium enhancement MRI is associated with sinus node dysfunction requiring pacemaker implant","volume":"23","author":"Akoum","year":"2012","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"2023072623574988700_bib2","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1113\/jphysiol.2002.027698","article-title":"Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node","volume":"549","author":"Altomare","year":"2003","journal-title":"J. Physiol."},{"key":"2023072623574988700_bib3","doi-asserted-by":"publisher","first-page":"7899","DOI":"10.1073\/pnas.1201997109","article-title":"Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels","volume":"109","author":"Bankston","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072623574988700_bib4","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1073\/pnas.1010122108","article-title":"Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4","volume":"108","author":"Baruscotti","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072623574988700_bib5","first-page":"ehv582","article-title":"A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial Inappropriate Sinus Tachycardia","author":"Baruscotti","year":"2015","journal-title":"Eur. Heart J."},{"key":"2023072623574988700_bib6","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1159\/000320454","article-title":"Inotropic effects of ivabradine in the mammalian heart","volume":"86","author":"Boldt","year":"2010","journal-title":"Pharmacology."},{"key":"2023072623574988700_bib7","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/ncpcardio0052","article-title":"Drug insight: If inhibitors as specific heart-rate-reducing agents","volume":"1","author":"Borer","year":"2004","journal-title":"Nat. Clin. Pract. Cardiovasc. Med."},{"key":"2023072623574988700_bib8","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.yjmcc.2007.04.017","article-title":"Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current","volume":"43","author":"Bucchi","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2023072623574988700_bib9","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1152\/japplphysiol.90401.2008","article-title":"Decreased maximal heart rate with aging is related to reduced \u03b2-adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate","volume":"105","author":"Christou","year":"2008","journal-title":"J. Appl. Physiol."},{"key":"2023072623574988700_bib10","doi-asserted-by":"publisher","first-page":"H1757","DOI":"10.1152\/ajpheart.00753.2003","article-title":"A rapidly activating delayed rectifier K+ current regulates pacemaker activity in adult mouse sinoatrial node cells","volume":"286","author":"Clark","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2023072623574988700_bib11","doi-asserted-by":"publisher","first-page":"37","DOI":"10.3389\/fphys.2015.00037","article-title":"Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction","volume":"6","author":"Csepe","year":"2015","journal-title":"Front. Physiol."},{"key":"2023072623574988700_bib12","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1161\/CIRCRESAHA.109.208041","article-title":"The role of the funny current in pacemaker activity","volume":"106","author":"DiFrancesco","year":"2010","journal-title":"Circ. Res."},{"key":"2023072623574988700_bib13","doi-asserted-by":"publisher","first-page":"4117","DOI":"10.1113\/jphysiol.2013.253765","article-title":"Funny channel gene mutations associated with arrhythmias","volume":"591","author":"DiFrancesco","year":"2013","journal-title":"J. Physiol."},{"key":"2023072623574988700_bib14","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/351145a0","article-title":"Direct activation of cardiac pacemaker channels by intracellular cyclic AMP","volume":"351","author":"DiFrancesco","year":"1991","journal-title":"Nature."},{"key":"2023072623574988700_bib15","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1161\/01.RES.0000218273.91741.30","article-title":"Compartmentation of cyclic nucleotide signaling in the heart: the role of A-kinase anchoring proteins","volume":"98","author":"Dodge-Kafka","year":"2006","journal-title":"Circ. Res."},{"key":"2023072623574988700_bib16","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1152\/jappl.1997.83.1.160","article-title":"Age-related declines in maximal aerobic capacity in regularly exercising vs. sedentary women: a meta-analysis","volume":"83","author":"Fitzgerald","year":"1997","journal-title":"J. Appl. Physiol."},{"key":"2023072623574988700_bib17","volume-title":"The Mouse in Biomedical Research: Normative Biology, Husbandry, and Models.","author":"Fox","year":"2007","edition":"Second edition"},{"key":"2023072623574988700_bib18","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1152\/jappl.1985.58.6.2041","article-title":"A hemodynamic comparison of young and older endurance athletes during exercise","volume":"58","author":"Hagberg","year":"1985","journal-title":"J. Appl. Physiol."},{"key":"2023072623574988700_bib19","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/BF00656997","article-title":"Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches","volume":"391","author":"Hamill","year":"1981","journal-title":"Pflugers Arch."},{"key":"2023072623574988700_bib20","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1161\/CIRCEP.110.960807","article-title":"TGF-\u03b21-mediated fibrosis and ion channel remodeling are key mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging","volume":"4","author":"Hao","year":"2011","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"2023072623574988700_bib21","doi-asserted-by":"publisher","first-page":"877","DOI":"10.2165\/00007256-200333120-00002","article-title":"Rate and mechanism of maximal oxygen consumption decline with aging: implications for exercise training","volume":"33","author":"Hawkins","year":"2003","journal-title":"Sports Med."},{"key":"2023072623574988700_bib22","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1152\/jappl.1981.51.3.634","article-title":"A physiological comparison of young and older endurance athletes","volume":"51","author":"Heath","year":"1981","journal-title":"J. Appl. Physiol."},{"key":"2023072623574988700_bib23","doi-asserted-by":"publisher","first-page":"4423","DOI":"10.1038\/sj.emboj.7601868","article-title":"HCN4 provides a \u2018depolarization reserve\u2019 and is not required for heart rate acceleration in mice","volume":"26","author":"Herrmann","year":"2007","journal-title":"EMBO J."},{"key":"2023072623574988700_bib24","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1111\/j.1476-5381.2011.01798.x","article-title":"HCN channels in the heart: Lessons from mouse mutants","volume":"166","author":"Herrmann","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"2023072623574988700_bib25","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1016\/0002-9149(86)90221-3","article-title":"Physiologic basis for the age-related decline in aerobic work capacity","volume":"57","author":"Higginbotham","year":"1986","journal-title":"Am. J. Cardiol."},{"key":"2023072623574988700_bib26","doi-asserted-by":"publisher","first-page":"H251","DOI":"10.1152\/ajpheart.00764.2010","article-title":"Minor contribution of cytosolic Ca2+ transients to the pacemaker rhythm in guinea pig sinoatrial node cells","volume":"300","author":"Himeno","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2023072623574988700_bib27","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s00395-007-0660-5","article-title":"Age-related down-regulation of HCN channels in rat sinoatrial node","volume":"102","author":"Huang","year":"2007","journal-title":"Basic Res. Cardiol."},{"key":"2023072623574988700_bib28","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1093\/cvr\/4.2.160","article-title":"The normal range and determinants of the intrinsic heart rate in man","volume":"4","author":"Jose","year":"1970","journal-title":"Cardiovasc. Res."},{"key":"2023072623574988700_bib29","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1016\/0002-8703(70)90254-1","article-title":"The effects of exercise and changes in body temperature on the intrinsic heart rate in man","volume":"79","author":"Jose","year":"1970","journal-title":"Am. Heart J."},{"key":"2023072623574988700_bib30","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1253\/jcj.57.760","article-title":"Age-related changes of sinus node function and autonomic regulation in subjects without sinus node disease--assessment by pharmacologic autonomic blockade","volume":"57","author":"Kuga","year":"1993","journal-title":"Jpn. Circ. J."},{"key":"2023072623574988700_bib31","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1161\/CIRCRESAHA.109.206078","article-title":"A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart\u2019s pacemaker","volume":"106","author":"Lakatta","year":"2010","journal-title":"Circ. Res."},{"key":"2023072623574988700_bib32","doi-asserted-by":"publisher","first-page":"18011","DOI":"10.1073\/pnas.1308477110","article-title":"Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate","volume":"110","author":"Larson","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072623574988700_bib33","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1085\/jgp.201010488","article-title":"Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node","volume":"136","author":"Liao","year":"2010","journal-title":"J. Gen. Physiol."},{"key":"2023072623574988700_bib34","doi-asserted-by":"publisher","first-page":"115","DOI":"10.4161\/chan.5.2.14195","article-title":"Myristoylated peptides potentiate the funny current (If) in sinoatrial myocytes","volume":"5","author":"Liao","year":"2011","journal-title":"Channels (Austin)."},{"key":"2023072623574988700_bib35","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1085\/jgp.201210858","article-title":"Cellular context and multiple channel domains determine cAMP sensitivity of HCN4 channels: Ligand-independent relief of autoinhibition in HCN4","volume":"140","author":"Liao","year":"2012","journal-title":"J. Gen. Physiol."},{"key":"2023072623574988700_bib36","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/978-1-59745-526-8_11","article-title":"Whole-cell recording using the perforated patch clamp technique","volume":"491","author":"Lippiat","year":"2008","journal-title":"Methods Mol. Biol."},{"key":"2023072623574988700_bib37","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/j.cardiores.2006.11.016","article-title":"Organisation of the mouse sinoatrial node: structure and expression of HCN channels","volume":"73","author":"Liu","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"2023072623574988700_bib38","doi-asserted-by":"publisher","first-page":"44811","DOI":"10.1074\/jbc.M111.297606","article-title":"Tetramerization dynamics of C-terminal domain underlies isoform-specific cAMP gating in hyperpolarization-activated cyclic nucleotide-gated channels","volume":"286","author":"Lolicato","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2023072623574988700_bib39","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/S0008-6363(01)00370-4","article-title":"Properties of the hyperpolarization-activated current (If) in isolated mouse sino-atrial cells","volume":"52","author":"Mangoni","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"2023072623574988700_bib40","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1152\/physrev.00018.2007","article-title":"Genesis and regulation of the heart automaticity","volume":"88","author":"Mangoni","year":"2008","journal-title":"Physiol. Rev."},{"key":"2023072623574988700_bib41","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1113\/jphysiol.2004.074047","article-title":"Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart","volume":"562","author":"Marionneau","year":"2005","journal-title":"J. Physiol."},{"key":"2023072623574988700_bib42","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1113\/jphysiol.2007.133439","article-title":"Ca2+-stimulated adenylyl cyclase isoform AC1 is preferentially expressed in guinea-pig sino-atrial node cells and modulates the If pacemaker current","volume":"582","author":"Mattick","year":"2007","journal-title":"J. Physiol."},{"key":"2023072623574988700_bib43","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.yjmcc.2011.08.016","article-title":"PDEs create local domains of cAMP signaling","volume":"52","author":"Mika","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2023072623574988700_bib44","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1046\/j.1432-1327.2001.02036.x","article-title":"Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues","volume":"268","author":"Moosmang","year":"2001","journal-title":"Eur. J. Biochem."},{"key":"2023072623574988700_bib45","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s11357-008-9048-1","article-title":"Design of aging intervention studies: the NIA interventions testing program","volume":"30","author":"Nadon","year":"2008","journal-title":"Age (Dordr.)."},{"key":"2023072623574988700_bib46","doi-asserted-by":"publisher","first-page":"2802","DOI":"10.1161\/01.CIR.0000146785.15995.67","article-title":"From mouse to whale: a universal scaling relation for the PR Interval of the electrocardiogram of mammals","volume":"110","author":"Noujaim","year":"2004","journal-title":"Circulation."},{"key":"2023072623574988700_bib47","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1161\/01.CIR.86.2.494","article-title":"Effects of aging, sex, and physical training on cardiovascular responses to exercise","volume":"86","author":"Ogawa","year":"1992","journal-title":"Circulation."},{"key":"2023072623574988700_bib48","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1113\/jphysiol.1992.sp019286","article-title":"Phosphorylation restores activity of L-type calcium channels after rundown in inside-out patches from rabbit cardiac cells","volume":"454","author":"Ono","year":"1992","journal-title":"J. Physiol."},{"key":"2023072623574988700_bib49","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1111\/apha.12077","article-title":"Compartmentation of cAMP signalling in cardiomyocytes in health and disease","volume":"207","author":"Perera","year":"2013","journal-title":"Acta Physiol. (Oxf.)."},{"key":"2023072623574988700_bib50","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/BF02011412","article-title":"Experimental studies of physical fitness in relation to age","volume":"10","author":"Robinson","year":"1938","journal-title":"Eur. J. Appl. Physiol."},{"key":"2023072623574988700_bib51","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1161\/01.CIR.0000139336.69955.AB","article-title":"Remodeling of sinus node function in patients with congestive heart failure: reduction in sinus node reserve","volume":"110","author":"Sanders","year":"2004","journal-title":"Circulation."},{"key":"2023072623574988700_bib52","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1016\/j.neuron.2009.05.009","article-title":"TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain","volume":"62","author":"Santoro","year":"2009","journal-title":"Neuron."},{"key":"2023072623574988700_bib53","doi-asserted-by":"publisher","first-page":"14577","DOI":"10.1073\/pnas.1410389111","article-title":"Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function","volume":"111","author":"Saponaro","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072623574988700_bib54","doi-asserted-by":"publisher","first-page":"4483","DOI":"10.1113\/jphysiol.2012.229435","article-title":"An updated computational model of rabbit sinoatrial action potential to investigate the mechanisms of heart rate modulation","volume":"590","author":"Severi","year":"2012","journal-title":"J. Physiol."},{"issue":"116","key":"2023072623574988700_bib55","first-page":"e54555","article-title":"Methods for the isolation, culture, and functional characterization of sinoatrial node myocytes from adult mice","author":"Sharpe","year":"2016","journal-title":"J. Vis. Exp."},{"key":"2023072623574988700_bib56","doi-asserted-by":"publisher","first-page":"318","DOI":"10.4161\/chan.25293","article-title":"PKA-independent activation of If by cAMP in mouse sinoatrial myocytes","volume":"7","author":"St Clair","year":"2013","journal-title":"Channels (Austin)."},{"key":"2023072623574988700_bib57","doi-asserted-by":"publisher","first-page":"H490","DOI":"10.1152\/ajpheart.00068.2015","article-title":"Culture and adenoviral infection of sinoatrial node myocytes from adult mice","volume":"309","author":"St Clair","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2023072623574988700_bib58","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1124\/mol.105.020701","article-title":"Bradycardic and proarrhythmic properties of sinus node inhibitors","volume":"69","author":"Stieber","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"2023072623574988700_bib59","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1161\/01.RES.0000251717.98379.69","article-title":"Differential expression of ion channel transcripts in atrial muscle and sinoatrial node in rabbit","volume":"99","author":"Tellez","year":"2006","journal-title":"Circ. Res."},{"key":"2023072623574988700_bib60","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1113\/expphysiol.2011.057752","article-title":"Ageing-dependent remodelling of ion channel and Ca2+ clock genes underlying sino-atrial node pacemaking","volume":"96","author":"Tellez","year":"2011","journal-title":"Exp. Physiol."},{"key":"2023072623574988700_bib61","doi-asserted-by":"publisher","first-page":"3071","DOI":"10.3390\/ijms16023071","article-title":"Pacemaker activity of the human sinoatrial node: an update on the effects of mutations in HCN4 on the hyperpolarization-activated current","volume":"16","author":"Verkerk","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"2023072623574988700_bib62","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1161\/01.RES.0000204575.94040.d1","article-title":"High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca2+ store oscillations and spontaneous beating of cardiac pacemaker cells","volume":"98","author":"Vinogradova","year":"2006","journal-title":"Circ. Res."},{"key":"2023072623574988700_bib63","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1016\/j.yjmcc.2007.02.008","article-title":"Characterization of sinoatrial node in four conduction system marker mice","volume":"42","author":"Viswanathan","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2023072623574988700_bib64","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1038\/35081088","article-title":"Molecular mechanism of cAMP modulation of HCN pacemaker channels","volume":"411","author":"Wainger","year":"2001","journal-title":"Nature."},{"key":"2023072623574988700_bib65","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1113\/jphysiol.2006.124891","article-title":"cAMP microdomains and L-type Ca2+ channel regulation in guinea-pig ventricular myocytes","volume":"580","author":"Warrier","year":"2007","journal-title":"J. Physiol."},{"key":"2023072623574988700_bib66","doi-asserted-by":"crossref","first-page":"H829","DOI":"10.1152\/ajpheart.2000.278.3.H829","article-title":"Meta-analysis of the age-associated decline in maximal aerobic capacity in men: relation to training status","volume":"278","author":"Wilson","year":"2000","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2023072623574988700_bib67","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1161\/CIRCRESAHA.110.231340","article-title":"Compartmentalization of \u03b2-adrenergic signals in cardiomyocytes","volume":"109","author":"Xiang","year":"2011","journal-title":"Circ. Res."},{"key":"2023072623574988700_bib68","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1111\/j.1476-5381.2009.00185.x","article-title":"cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies","volume":"158","author":"Zaccolo","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"2023072623574988700_bib69","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/nature01922","article-title":"Structural basis for modulation and agonist specificity of HCN pacemaker channels","volume":"425","author":"Zagotta","year":"2003","journal-title":"Nature."},{"key":"2023072623574988700_bib70","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1016\/j.neuron.2009.05.008","article-title":"Association with the auxiliary subunit PEX5R\/Trip8b controls responsiveness of HCN channels to cAMP and adrenergic stimulation","volume":"62","author":"Zolles","year":"2009","journal-title":"Neuron."}],"container-title":["Journal of General Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/149\/2\/237\/1796443\/jgp_201611674.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/149\/2\/237\/1796443\/jgp_201611674.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T19:58:22Z","timestamp":1690401502000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jgp\/article\/149\/2\/237\/43580\/Cyclic-AMP-reverses-the-effects-of-aging-on"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,5]]},"references-count":70,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2017,2,1]]}},"URL":"https:\/\/doi.org\/10.1085\/jgp.201611674","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.727177643.793534099","asserted-by":"object"}]},"ISSN":["0022-1295","1540-7748"],"issn-type":[{"value":"0022-1295","type":"print"},{"value":"1540-7748","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,5]]}}}