cAMP signaling affects age-associated deterioration of pacemaker beating interval dynamics

Sofia Segal, Ori Shemla, Rotem Shapira, Noa Kirschner Peretz, Yevgeniya Lukyanenko, Inbar Brosh, Joachim Behar, Edward G. Lakatta, Kenta Tsutsui, Yael Yaniv

Research output: Contribution to journalArticlepeer-review


Sinoatrial node (SAN) beating interval variability (BIV) and the average beating interval (BI) are regulated by a coupled-clock system, driven by Ca2+-calmodulin activated adenylyl cyclase, cAMP, and downstream PKA signaling. Reduced responsiveness of the BI and BIV to submaximal, [X]50, β-adrenergic receptor (β-AR) stimulation, and phosphodiesterase inhibition (PDEI) have been documented in aged SAN tissue, whereas the maximal responses, [X]max, do not differ by age. To determine whether age-associated dysfunction in cAMP signaling leads to altered responsiveness of BI and BIV, we measured cAMP levels and BI in adult (2–4 months n = 27) and aged (22–26 months n = 25) C57/BL6 mouse SAN tissue in control and in response to β-AR or PDEI at X50 and [X]max. Both cAMP and average BI in adult SAN were reduced at X50, whereas cAMP and BI at Xmax did not differ by age. cAMP levels and average BI were correlated both within and between adult and aged SAN. BIV parameters in long- and short-range terms were correlated with cAMP levels for adult SAN. However, due to reduced cAMP within aged tissues at [X]50, these correlations were diminished in advanced age. Thus, cAMP level generated by the coupled clock mechanisms is tightly linked to average BI. Reduced cAMP level at X50 in aged SAN explains the reduced responsiveness of the BI and BIV to β-AR stimulation and PDEI.

Original languageEnglish
Pages (from-to)2589-2600
Number of pages12
Issue number4
StatePublished - 21 Apr 2023


  • Aging
  • Beating rate
  • Pacemaker
  • cAMP

All Science Journal Classification (ASJC) codes

  • Ageing
  • veterinary (miscalleneous)
  • Complementary and alternative medicine
  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'cAMP signaling affects age-associated deterioration of pacemaker beating interval dynamics'. Together they form a unique fingerprint.

Cite this