Autonomic modulation of sinoatrial node: Role of pacemaker current and calcium sensitive adenylyl cyclase isoforms

doi:10.1016/j.pbiomolbio.2020.08.004

Progress in Biophysics and Molecular Biology

Volume 166, November 2021, Pages 22-28

https://doi.org/10.1016/j.pbiomolbio.2020.08.004 Get rights and content

Abstract

This article reviews work over the past three decades that is related to the contribution of the pacemaker current, I_f, to basal and autonomically regulated spontaneous rate in the sinoatrial node. It also addresses how the actions of the pacemaker current relate to those of Ca homeostasis with respect to basal and autonomically regulated rhythm. In this regard, it explores the relative contributions of Ca-sensitive and Ca-insensitive isoforms of adenylyl cyclase to sinoatrial node automaticity. The latter studies include previously unpublished work making use of mice in which both the type 1 and type 8 Ca-sensitive adenylyl cyclase isoforms were knocked out. These studies indicate that the pacemaker current and the L-type Ca current are distinctly influenced by Ca-sensitive and insensitive adenylyl cyclase isoforms.

Section snippets

Autonomic responsiveness in sinoatrial node

In 1986, the DiFrancesco laboratory described the pacemaker current I_f, and its regulation by catecholamines in the sinoatrial node (SAN) (DiFrancesco, 1986; DiFrancesco et al., 1986). In 1987 this laboratory went on to report the effect of acetylcholine (ACh) on the current (DiFrancesco and Tromba, 1987). Since then, there has been continuing debate on the relative contribution of I_f to basal and autonomically regulated rate in SAN.

In 1989, one of us co-authored a study with DiFrancesco

Calcium sensitivity of adrenergic signaling

Subsequently, the group of Lakatta and colleagues argued that the most important contribution to both basal and autonomically stimulated rate in SAN cells results from changes in Ca homeostasis and the Na/Ca exchange current (Bogdanov et al., 2001). The key observation underlying this argument is that depletion of intracellular Ca stores by ryanodine (RY) reduces both basal SAN rate and eliminates the stimulatory effect of β-adrenergic agonists on rate.

In further collaboration with the

Studies in adenylyl cyclase knockout mice

While the above experiments were suggestive, they were conducted in a preparation (neonatal rat ventricle cells in culture) that might not be strictly applicable to the SAN. To address this possible limitation, we obtained mice in which the Ca-sensitive AC isoforms AC1 and AC8 were both knocked out (Zachariou et al., 2008). These double knockout animals (DKO) were provided by Dr. D.R. Storm of the University of Washington and when used were compared to commercially obtained strain-matched wild

Discussion and limitations

The debate on the relative contributions of different mechanisms to SAN basal and autonomically regulated automaticity continues, with recent discussions focusing on the “membrane” vs “Ca clock” mechanisms (Lakatta and DiFrancesco, 2009). However, there are some aspects that can probably be largely agreed upon. First, studies expressing members of the HCN gene family in the heart using viral vectors or stem cells for delivery (Robinson et al., 2006; Rosen et al., 2011) demonstrate that, under

Author statement

All authors were involved in collecting/analyzing/reviewing data and in the drafting and review of the manuscript text.

Declaration of competing interest

None.

Acknowledgements

We thank Dr. D.R. Storm of the University of Washington for providing the AC1/AC8 double knockout mice used in these studies. We also acknowledge the contributions of the late Dr. Lev Protas to some of the experimental results. Previously published data reproduced herein were generated with the support of NIH grants HL-28958 and HL-094410.

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Citation Excerpt :
We reported that 2-month- and 12-month-old mice overexpressing AC8 display higher HR than WT mice ubder basal conditions (Mougenot et al., 2019). These data are consistent with findings obtained in double AC1 and AC8 KO mice showing that removing Ca2+-sensitive adenylyl cyclase isoforms in SAN cells alters currents relevant to automaticity (Robinson et al., 2020). Another element at the junction between Ca2+ and cAMP pathways is PDE1, that has the property to be directly regulated by Ca2+ (activated by CaM complex or CaMKII phosphorylation).
The sinoatrial node (SAN) is the natural pacemaker of the heart, producing the electrical impulse that initiates every heart beat. Its activity is tightly controlled by the autonomic nervous system, and by circulating and locally released factors. Neurohumoral regulation of heart rate plays a crucial role in the integration of vital functions and influences behavior and ability to respond to changing environmental conditions. At the cellular level, modulation of SAN activity occurs through intracellular signaling pathways involving cyclic nucleotides: cyclic AMP (cAMP) and cyclic GMP (cGMP). In this Review, dedicated to Professor Dario DiFrancesco and his accomplishements in the field of cardiac pacemaking, we summarize all findings on the role of cyclic nucleotides signaling in regulating the key actors of cardiac automatism, and we provide an up-to-date review on cAMP- and cGMP-phosphodiesterases (PDEs), compellingly involved in this modulation.
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Original ResearchAutonomic modulation of sinoatrial node: Role of pacemaker current and calcium sensitive adenylyl cyclase isoforms

Abstract

Section snippets

Autonomic responsiveness in sinoatrial node

Calcium sensitivity of adrenergic signaling

Studies in adenylyl cyclase knockout mice

Discussion and limitations

Author statement

Declaration of competing interest

Acknowledgements

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

Pharmacol. Res.

J. Biol. Chem.

Biol. Psychiatr.

Function of adenylyl cyclase in heart: the AKAP connection

J. Cardiovasc. Dev. Dis.

Sinoatrial nodal cell ryanodine receptor and Na(+)-Ca(2+) exchanger: molecular partners in pacemaker regulation

Circ. Res.

Characterization of single pacemaker channels in cardiac sino-atrial node cells

Nature

Muscarinic modulation of cardiac rate at low acetylcholine concentrations

Science

Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node

J. Physiol. (London)

Direct activation of cardiac pacemaker channels by intracellular cyclic AMP

Nature

Acetylcholine inhibits activation of the cardiac hyperpolarizing-activated current, if

Pflügers Archiv

Original Research
Autonomic modulation of sinoatrial node: Role of pacemaker current and calcium sensitive adenylyl cyclase isoforms

Properties of the hyperpolarizing-activated current (i_f) in cells isolated from the rabbit sino-atrial node

Acetylcholine inhibits activation of the cardiac hyperpolarizing-activated current, i_f