Cyclic nucleotide signaling and pacemaker activity

Mika, Delphine; Fischmeister, Rodolphe

doi:10.1016/j.pbiomolbio.2021.07.007

Cited by 7 publications

(5 citation statements)

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“…Although the role of the cAMP-dependent protein kinase (PKA)-induced phosphorylation of pacemaker channels is still an open issue ( Mika and Fischmeister, 2021 ), a relevant study by Liao et al, 2010 shows that in mice SAN cells PKA modulates the voltage dependence of I f . We thus tested whether the effect of TMYX (2 mg/ml) on basal cell rate was dependent upon PKA activity.…”

Section: Resultsmentioning

confidence: 99%

“…cAMP synthesis is operated by the Ca 2+ -sensitive and Ca 2+ -insensitive adenylyl cyclase (AC1/8 and AC5/6, respectively), while cAMP conversion to AMP is catalyzed by the action of the PDE. AC and PDE are therefore central elements of a regulatory pathway that controls cell cAMP dynamics at rest and during autonomic stimulation ( Mika and Fischmeister, 2021 ; Robinson et al, 2021 ; Sirenko et al, 2021 ; Yaniv et al, 2015 ). According to St Clair et al, 2017 , PDE4 is particularly relevant in basal conditions, while PDE3 activity is important during β-adrenergic stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…According to St Clair et al, 2017 , PDE4 is particularly relevant in basal conditions, while PDE3 activity is important during β-adrenergic stimulation. A further level of physiological refinement is provided by the evidence that pacemaker channels are localized in caveolar structures ( Barbuti et al, 2004 ; Barbuti et al, 2012 ), and this compartmentalization ensures the existence of functional microdomains where cAMP oscillations may differ from those occurring in the bulk of the cytoplasm ( Mika and Fischmeister, 2021 ). Taken together these regulatory pathways control cAMP levels, hence SAN rate, in pacemaker cells.…”

Section: Discussionmentioning

confidence: 99%

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Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels

Piantoni

Paina

Molla

et al. 2022

eLife

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Tongmai Yangxin (TMYX) is a complex compound of the Traditional Chinese Medicine (TCM) used to treat several cardiac rhythm disorders; however, no information regarding its mechanism of action is available. In this study we provide a detailed characterization of the effects of TMYX on the electrical activity of pacemaker cells and unravel its mechanism of action. Single-cell electrophysiology revealed that TMYX elicits a reversible and dose-dependent (2/6 mg/ml) slowing of spontaneous action potentials rate (−20.8/–50.2%) by a selective reduction of the diastolic phase (−50.1/–76.0%). This action is mediated by a negative shift of the If activation curve (−6.7/–11.9 mV) and is caused by a reduction of the cyclic adenosine monophosphate (cAMP)-induced stimulation of pacemaker channels. We provide evidence that TMYX acts by directly antagonizing the cAMP-induced allosteric modulation of the pacemaker channels. Noticeably, this mechanism functionally resembles the pharmacological actions of muscarinic stimulation or β-blockers, but it does not require generalized changes in cytoplasmic cAMP levels thus ensuring a selective action on rate. In agreement with a competitive inhibition mechanism, TMYX exerts its maximal antagonistic action at submaximal cAMP concentrations and then progressively becomes less effective thus ensuring a full contribution of If to pacemaker rate during high metabolic demand and sympathetic stimulation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels

Piantoni

Paina

Molla

et al. 2022

eLife

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“… 27 , 48 , 102 M 2 mAChR-stimulated, as well as adenosine receptor-stimulated, Gαi-dependent inhibition of adenylyl cyclase also contributes to cholinergic (and adenosinergic) slowing of HR since cAMP is essential for the operation of hyperpolarization-activated cyclic Nucleotide-gated (HCN)-4 channels, responsible for the generation of the pacemaker ‘funny’ current (If) in SA nodal pacemaker cells. 103 , 104 cAMP also enhances depolarizing Ca 2+ influx currents in AV nodal cells ( via PKA-mediated phosphorylation and opening of L-type calcium channels and of ryanodine receptor 2 channels), which is responsible for propagation of electrical conduction throughout the atria, AV node, and over to the ventricles (Purkinje fibers and Hiss bundle). 26 , 27 , 94 , 105 In other words, cAMP lowering reduces automaticity and induces negative dromotropy in the heart.…”

Section: Therapeutic Potential Of Cardiac Rgs4mentioning

confidence: 99%

The therapeutic potential of targeting cardiac RGS4

Del Calvo,

Baggio Lopez,

Lymperopoulos

2023

Therapeutic Advances in Cardiovascular Disease

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G protein-coupled receptors (GPCRs) play pivotal roles in regulation of cardiac function and homeostasis. To function properly, every cell needs these receptors to be stimulated only when a specific extracellular stimulus is present, and to be silenced the moment that stimulus is removed. The regulator of G protein signaling (RGS) proteins are crucial for the latter to occur at the cell membrane, where the GPCR normally resides. Perturbations in both activation and termination of G protein signaling underlie numerous heart pathologies. Although more than 30 mammalian RGS proteins have been identified, each RGS protein seems to interact only with a specific set of G protein subunits and GPCR types/subtypes in any given tissue or cell type, and this applies to the myocardium as well. A large number of studies have provided substantial evidence for the roles various RGS proteins expressed in cardiomyocytes play in cardiac physiology and heart disease pathophysiology. This review summarizes the current understanding of the functional roles of cardiac RGS proteins and their implications for the treatment of specific heart diseases, such as heart failure and atrial fibrillation. We focus on cardiac RGS4 in particular, since this isoform appears to be selectively (among the RGS protein family) upregulated in human heart failure and is also the target of ongoing drug discovery efforts for the treatment of a variety of diseases.

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“…This arrangement allows a pulse of cAMP to briefly breach the threshold of activation of the anchored PKA within each complex and deliver a transient augmentation of calcium flux following phosphorylation of the respective PKA substrates. The anchored PDE influences the size and duration of the local PKA drive whilst also guarding against inappropriate activation at resting heart rate [ 11 ]. There are many other non-cardiac examples of cAMP effectors (PKA, EPAC and cyclic nucleotide-gated (CNG) channels) that exist in complex with PDEs (reviewed in [ 8 ]).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase type 4 anchoring regulates cAMP signaling to Popeye domain-containing proteins

Tibbo

Mika

Dobi

et al. 2022

Journal of Molecular and Cellular Cardiology

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Cyclic AMP is a ubiquitous second messenger used to transduce intracellular signals from a variety of Gs-coupled receptors. Compartmentalisation of protein intermediates within the cAMP signaling pathway underpins receptor-specific responses. The cAMP effector proteins protein-kinase A and EPAC are found in complexes that also contain phosphodiesterases whose presence ensures a coordinated cellular response to receptor activation events. Popeye domain containing (POPDC) proteins are the most recent class of cAMP effectors to be identified and have crucial roles in cardiac pacemaking and conduction. We report the first observation that POPDC proteins exist in complexes with members of the PDE4 family in cardiac myocytes. We show that POPDC1 preferentially binds the PDE4A sub-family via a specificity motif in the PDE4 UCR1 region and that PDE4s bind to the Popeye domain of POPDC1 in a region known to be susceptible to a mutation that causes human disease. Using a cell-permeable disruptor peptide that displaces the POPDC1-PDE4 complex we show that PDE4 activity localized to POPDC1 modulates cycle length of spontaneous Ca 2+ transients firing in intact mouse sinoatrial nodes.

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Cyclic nucleotide signaling and pacemaker activity

Cited by 7 publications

References 128 publications

Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels

Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels

The therapeutic potential of targeting cardiac RGS4

Phosphodiesterase type 4 anchoring regulates cAMP signaling to Popeye domain-containing proteins

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