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CAMP signaling affects age-associated deterioration of pacemaker beating interval dynamics.

ABSTRACT: 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 X_max 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.

SUBMITTER: Segal S

PROVIDER: S-EPMC10651572 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Segal Sofia S Shemla Ori O Shapira Rotem R Peretz Noa Kirschner NK Lukyanenko Yevgeniya Y Brosh Inbar I Behar Joachim J Lakatta Edward G EG Tsutsui Kenta K Yaniv Yael Y

GeroScience 20230421 4

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 ...[more]

PMID: 37084120

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Project description:Age-related deterioration of pacemaker function has been documented in mammals, including humans. In aged isolated sinoatrial node tissues and cells, reduction in the spontaneous action potential (AP) firing rate was associated with deterioration of intracellular and membrane mechanisms; however, their relative contribution to age-associated deficient pacemaker function is not known. Interestingly, pharmacological interventions that increase posttranslation modification signaling activities can restore the basal and maximal AP firing rate, but the identities of the protein targets responsible for AP firing rate restoration are not known. Here, we developed a numerical model that simulates the function of a single mouse pacemaker cell. In addition to describing membrane and intracellular mechanisms, the model includes descriptions of autonomic receptor activation pathways and posttranslation modification signaling cascades. The numerical model shows that age-related deterioration of pacemaker function is related to impaired intracellular and membrane mechanisms: HCN4, T-type channels, and phospholamban functions, as well as the node connecting these mechanisms, i.e., intracellular Ca2+ and posttranslation modification signaling. To explain the restored maximal beating rate in response to maximal phosphodiesterase (PDE) inhibition, autonomic receptor stimulation, or infused cyclic adenosine monophosphate (cAMP), the model predicts that phospholamban phosphorylation by protein kinase A (PKA) and HCN4 sensitivity to cAMP are altered in advanced age. Moreover, alteration in PKA and cAMP sensitivity can also explain age-reduced sensitivity to PDE inhibition and autonomic receptor stimulation. Finally, the numerical model suggests two pharmacological approaches and one gene manipulation method to restore the basal beating rate of aged pacemaker cells to that of normal adult cells. In conclusion, our numerical model shows that impaired membrane and intracellular mechanisms and the nodes that couple them can lead to deteriorated pacemaker function. By increasing posttranslation modification signaling, the deteriorated basal and maximal age-associated beating rate can be restored to adult levels.

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CAMP signaling affects age-associated deterioration of pacemaker beating interval dynamics.

Publications

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

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