title: Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca(2+) signaling.
abstract: A reduced sinoatrial node (SAN) functional reserve underlies the age-associated decline in heart rate acceleration in response to stress. SAN cell function involves an oscillatory coupled-clock system: the sarcoplasmic reticulum (SR), a Ca(2+) clock, and the electrogenic-sarcolemmal membrane clock. Ca(2+)-activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca(2+) signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na(+)/Ca(2+) exchanger in the membrane clock, which initiates the action potential (AP). We hypothesize that SAN cell dysfunctions accumulate with age. We found a reduction in single SAN cell AP firing in aged (20-24 mo) vs. adult (3-4 mo) mice. The sensitivity of the SAN beating rate responses to both muscarinic and adrenergic receptor activation becomes decreased in advanced age. Additionally, age-associated coincident dysfunctions occur stemming from compromised clock functions, including a reduced SR Ca(2+) load and a reduced size, number, and duration of spontaneous LCRs. Moreover, the sensitivity of SAN beating rate to a cAMP stress induced by phosphodiesterase inhibitor is reduced, as are the LCR size, amplitude, and number in SAN cells from aged vs. adult mice. These functional changes coincide with decreased expression of crucial SR Ca(2+)-cycling proteins, including SR Ca(2+)-ATPase pump, ryanodine receptors, and Na(+)/Ca(2+) exchanger. Thus a deterioration in intrinsic Ca(2+) clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca(2+) cycling and its response to a cAMP-dependent pathway activation, is involved in the age-associated reduction in intrinsic resting AP firing rate, and in the reduction in the acceleration of heart rate during exercise.
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and Department of Physiology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and.
authors.forename: Syevda
authors.initials: S
authors.lastname: Sirenko
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Juhaszova
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Sollott
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and.
authors.forename: Shweta
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and.
authors.forename: Yael
authors.initials: Y
authors.lastname: Yaniv
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; and LakattaE@grc.nia.nih.gov.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000172:deficiency* / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000172:deficiency / Q000502:physiology; D000242:Cyclic AMP / Q000172:deficiency* / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000172:deficiency* / Q000502:physiology; D006339:Heart Rate / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D012849:Sinoatrial Node / Q000503:physiopathology*; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Ca2+ transient; PKA signaling; aging; intrinsic heart rate; pacemaker function