alexa Age Associated Decrease in Intrinsic Action Potential (AP) Firing Rate in Sinoatrial Node Cells is Linked to Deficient Intrinsic cAMP-PKA-Ca2+ Signaling
Clinical Sciences

Clinical Sciences

Cardiovascular Pharmacology: Open Access

Author(s): Syevda Sirenko, Jie Liu, Edward G Lakatta, Shweta Shukla

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Constitutive cAMP-PKA signaling to sarcoplasmic reticulum (SR) in sinoatrial nodal cells (SANC) generates spontaneous, rhythmic local Ca2+ releases (LCRs) beneath the surface membrane, that underlie the Action Potential (AP) Intrinsic Firing Rate (IAPFR). IAPFR in vivo, and in isolated sinoatrial nodes (SAN) declines between 2-4 and 22-24 months in C57 black mice and augmentation of AP firing rate in response to phophodiesterase (PDE) inhibition, which prevents cAMP degradation and augments PKA-dependent phosphorylation of SR Ca2+ cycling proteins, declines with age. We tested whether the response SR Ca2+ cycling to cAMP-PKA signaling declines with age. To study the SR Ca2+ cycling at clamped [Ca2+]i (100 nmol/L ) we permeabilized single SANC with 0.01% saponin. The frequency of spontaneous LCRs was substantially lower in SANC of old (48.6±5.3/sec∗μm, n=10) vs. young mice (80.9±11/sec∗μm, n=11). The caffeine induced releasable Ca2+ (rapid spritz, 20 mM) also decreased with age: 77.7±12.6 nmol/L (n=5) in old vs. 120.7±10.8 nmol/L (n=8) in young. Incubation with the broad spectrum PDE inhibitor, IBMX (5µM), significantly (p<0.03) increased LCR's size (4.4 to 7±0.5µm), duration (38 to 56±3.6ms), the integral of LCR Ca2+ release (Σ∗µm∗ms∗ΔCa2+ nmol/L) and estimated number of active RyR clusters (more than 2 fold), the rhythmicity index (RI, assessed via autocorrelation function) increased in young (n=11), but not in old SANC (p>0.05 n=7). Phospholamban (PLB) phosphorylation at Ser16 (PLB/total PLB) immunolabeling in control did not differ with age, but increased 2.2±0.2 fold after incubation with 10 μM IBMX in young but did not increase in old SANC (p<0.05). We conclude that intrinsic SR Ca2+cycling and its response to PDE inhibition decline with age, and that this decline is linked to the age-associated decrease in IAPFR.

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This article was published in Biophysical Journal and referenced in Cardiovascular Pharmacology: Open Access

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