Basal Spontaneous Firing of Rabbit Sinoatrial Node Cells Is Regulated by Dual Activation of PDEs (Phosphodiesterases) 3 and 4

Vinogradova, Tatiana M.; Sirenko, Syevda; Lukyanenko, Yevgeniya O.; Yang, Dongmei; Tarasov, Kirill V.; Lyashkov, Alexey E.; Varghese, Nevin; Li, Yue; Chakir, Khalid; Ziman, Bruce D.; Lakatta, Edward G.

doi:10.1161/circep.117.005896

Cited by 24 publications

(68 citation statements)

References 51 publications

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“…Under the conditions of our study, inhibition of ACs or PKA significantly reduced baseline stimulated Ca 2+ transient amplitude in atrial myocytes and beating rate in right atrial preparations. This is consistent with published data from our group (Mattick et al, 2007;Collins & Terrar, 2012) and others Vinogradova et al, 2018).…”

Section: Discussionsupporting

confidence: 94%

cAMP signalling is required for the actions of IP₃on Ca²⁺-transients in cardiac atria and beating rate in sino-atrial node

Capel

Collins

Bose

et al. 2019

Preprint

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Inositol trisphosphate (IP3) is a major Ca 2+ -mobilising second messenger and atrial IP3 receptor (IP3R) expression is greatly increased in atrial fibrillation (AF). Cardiac atrial and sino-atrial node myocytes also express Ca 2+ -stimulated adenylyl cyclases (AC1 and AC8); however the physiological pathways underlying AC1 and AC8 activation are not known. We investigated whether IP3 signalling in cardiac atria and sino-atrial node utilises ACs.Immunocytochemistry in isolated guinea pig atrial myocytes showed type 2 IP3Rs colocalised with AC8, while AC1 was located in close vicinity. UV photorelease of IP3 significantly enhanced Ca 2+ transient amplitudes following stimulation of atrial myocytes (31 ± 6 % increase 60 s post photorelease, n=16), an effect abolished by 3 µmol/L MDL-12,330 (MDL), to inhibit ACs, or 1 µmol/L H89, to inhibit PKA. The maximum rate change observed in spontaneously-beating murine right atrial preparations exposed to phenylephrine (14.7 ± 0.5 %, n=10) was significantly reduced by 2.5 µmol/L 2-APB (to 4.7 ± 0.2 %, n=7, P<0.05 compared to control) and abolished by a low dose of MDL (1 µmol/L, n=5). These observations are consistent with a functional interaction between IP3 and cAMP signalling involving Ca 2+ stimulation of ACs in cardiac atria and sino-atrial node. Structural evidence supports AC8 as the most likely effector. This signal transduction mechanism is important for future study in atrial physiology and pathophysiology, particularly AF.

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Section: Discussionsupporting

confidence: 94%

cAMP signalling is required for the actions of IP₃on Ca²⁺-transients in cardiac atria and beating rate in sino-atrial node

Capel

Collins

Bose

et al. 2019

Preprint

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“…Concurrent PDE3 and PDE4 activation modulates Ca 2+ -clock components, specifically via a decrease in cAMP and PKA phosphorylation, which suppresses local Ca 2+ releases and decreases HR (Vinogradova et al, 2018b). Following blockade of RyR with ryanodine, dual PDE3 and PDE4 inhibition failed to increase spontaneous HR, implicating that modulation of the Ca 2+ -clock is necessary for basal synergistic effects of PDE3 and PDE4 on HR (Vinogradova et al, 2018b).…”

Section: Intracellular Compartmentalizationmentioning

confidence: 98%

“…Although inhibition of single PDEs only moderately increases SAN myocyte firing, recently it has been shown that dual PDE3 and PDE4 inhibition synergistically increases basal SAN firing rate by ∼50% (Vinogradova et al, 2018a). Concurrent PDE3 and PDE4 activation modulates Ca 2+ -clock components, specifically via a decrease in cAMP and PKA phosphorylation, which suppresses local Ca 2+ releases and decreases HR (Vinogradova et al, 2018b). Following blockade of RyR with ryanodine, dual PDE3 and PDE4 inhibition failed to increase spontaneous HR, implicating that modulation of the Ca 2+ -clock is necessary for basal synergistic effects of PDE3 and PDE4 on HR (Vinogradova et al, 2018b).…”

Section: Intracellular Compartmentalizationmentioning

confidence: 99%

Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans

2020

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The sinoatrial node is perhaps one of the most important tissues in the entire body: it is the natural pacemaker of the heart, making it responsible for initiating each-andevery normal heartbeat. As such, its activity is heavily controlled, allowing heart rate to rapidly adapt to changes in physiological demand. Control of sinoatrial node activity, however, is complex, occurring through the autonomic nervous system and various circulating and locally released factors. In this review we discuss the coupled-clock pacemaker system and how its manipulation by neurohumoral signaling alters heart rate, considering the multitude of canonical and non-canonical agents that are known to modulate sinoatrial node activity. For each, we discuss the principal receptors involved and known intracellular signaling and protein targets, highlighting gaps in our knowledge and understanding from experimental models and human studies that represent areas for future research.

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“…One-way ANOVA with Bonferroni post hoc test ∗ P < 0.01 vs. rolipram alone; + P < 0.01 vs. cilostamide alone. (C,E,F) Modified from Vinogradova et al (2008 , 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…A synergistic relationship between PDE3 and PDE4 inhibition has been noted in different cell types, including vascular smooth muscle cells ( Palmer et al, 1998 ), brown adipose tissue ( Kraynik et al, 2013 ), and rat VM ( Mika et al, 2013 ). Normal automaticity of rabbit SANC is regulated by dual PDE3 + PDE4 activation apparently operating in a synergistic manner ( Vinogradova et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Dual Activation of Phosphodiesterases 3 and 4 Regulates Basal Spontaneous Beating Rate of Cardiac Pacemaker Cells: Role of Compartmentalization?

2018

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Spontaneous firing of sinoatrial (SA) node cells (SANCs) is regulated by cyclic adenosine monophosphate (cAMP)-mediated, protein kinase A (PKA)-dependent (cAMP/PKA) local subsarcolemmal Ca2+ releases (LCRs) from ryanodine receptors (RyR). The LCRs occur during diastolic depolarization (DD) and activate an inward Na+/Ca2+ exchange current that accelerates the DD rate prompting the next action potential (AP). Basal phosphodiesterases (PDEs) activation degrades cAMP, reduces basal cAMP/PKA-dependent phosphorylation, and suppresses normal spontaneous firing of SANCs. The cAMP-degrading PDE1, PDE3, and PDE4 represent major PDE activities in rabbit SANC, and PDE inhibition by 3-isobutyl-1-methylxanthine (IBMX) increases spontaneous firing of SANC by ∼50%. Though inhibition of single PDE1–PDE4 only moderately increases spontaneous SANC firing, dual PDE3 + PDE4 inhibition produces a synergistic effect hastening the spontaneous SANC beating rate by ∼50%. Here, we describe the expression and distribution of different PDE subtypes within rabbit SANCs, several specific targets (L-type Ca2+ channels and phospholamban) regulated by basal concurrent PDE3 + PDE4 activation, and critical importance of RyR Ca2+ releases for PDE-dependent regulation of spontaneous SANC firing. Colocalization of PDE3 and PDE4 beneath sarcolemma or in striated patterns inside SANCs strongly suggests that PDE-dependent regulation of cAMP/PKA signaling might be executed at the local level; this idea, however, requires further verification.

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Basal Spontaneous Firing of Rabbit Sinoatrial Node Cells Is Regulated by Dual Activation of PDEs (Phosphodiesterases) 3 and 4

Abstract: Basal cardiac pacemaker function is regulated by concurrent PDE3+PDE4 activation which operates in a synergistic manner via decrease in cAMP/PKA phosphorylation, suppression of LCR parameters, and prolongation of the LCR period and spontaneous SANC cycle length.

Cited by 24 publications

References 51 publications

cAMP signalling is required for the actions of IP₃on Ca²⁺-transients in cardiac atria and beating rate in sino-atrial node

cAMP signalling is required for the actions of IP₃on Ca²⁺-transients in cardiac atria and beating rate in sino-atrial node

Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans

Dual Activation of Phosphodiesterases 3 and 4 Regulates Basal Spontaneous Beating Rate of Cardiac Pacemaker Cells: Role of Compartmentalization?

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Basal Spontaneous Firing of Rabbit Sinoatrial Node Cells Is Regulated by Dual Activation of PDEs (Phosphodiesterases) 3 and 4

Abstract: Basal cardiac pacemaker function is regulated by concurrent PDE3+PDE4 activation which operates in a synergistic manner via decrease in cAMP/PKA phosphorylation, suppression of LCR parameters, and prolongation of the LCR period and spontaneous SANC cycle length.

Cited by 24 publications

References 51 publications

cAMP signalling is required for the actions of IP3on Ca2+-transients in cardiac atria and beating rate in sino-atrial node

cAMP signalling is required for the actions of IP3on Ca2+-transients in cardiac atria and beating rate in sino-atrial node

Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans

Dual Activation of Phosphodiesterases 3 and 4 Regulates Basal Spontaneous Beating Rate of Cardiac Pacemaker Cells: Role of Compartmentalization?

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cAMP signalling is required for the actions of IP₃on Ca²⁺-transients in cardiac atria and beating rate in sino-atrial node

cAMP signalling is required for the actions of IP₃on Ca²⁺-transients in cardiac atria and beating rate in sino-atrial node