Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cells

Borren, Marcel M. G. J. van; Verkerk, Arie O.; Wilders, Ronald; Hajji, Najat; Zegers, Jan G.; Bourier, Jan; Tan, Hanno L.; Verheijck, E. E.; Peters, Stephan L. M.; Alewijnse, Astrid E.; Ravesloot, Jan H.

doi:10.1007/s00395-009-0048-9

Cited by 49 publications

(55 citation statements)

References 53 publications

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“…54) have been mainly based on a H-H-type membrane voltage oscillator, the present numerical study revealed that the rate of spontaneous APs in cardiac pacemaker cells is modulated by GPCR signaling via a complex dynamic integration of voltage-and Ca 2ϩ -dependent processes within the SANC system (Fig. 8), consistent with experimental results (32,47,49,50,55) and recent reviews (27,34). The shifts (marked by ⌬) in the balance of system components (which ultimately determine the chronotropic response) are looped and are thus interdependent.…”

Section: Discussionsupporting

confidence: 87%

“…Previous experimental results (32,47) have shown that the mechanism of SANC rate slowing via ChR activation is complex and includes changes in both sarcolemmal ion currents and diastolic Ca 2ϩ release. Electrophysiological changes include PKA-dependent I CaL reduction (43,56), a shift of cAMPdependent I f activation toward negative potentials (9, 10), and G i -dependent activation of I KACh (6, 12) (Fig.…”

Section: Prediction Of Chr Stimulationmentioning

confidence: 99%

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A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins

Maltsev

Lakatta

2010

American Journal of Physiology-Heart and Circulatory Physiology

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Classical numerical models have attributed the regulation of normal cardiac automaticity in sinoatrial node cells (SANCs) largely to G protein-coupled receptor (GPCR) modulation of sarcolemmal ion currents. More recent experimental evidence, however, has indicated that GPCR modulation of SANCs automaticity involves spontaneous, rhythmic, local Ca(2+) releases (LCRs) from the sarcoplasmic reticulum (SR). We explored the GPCR rate modulation of SANCs using a unique and novel numerical model of SANCs in which Ca(2+)-release characteristics are graded by variations in the SR Ca(2+) pumping capability, mimicking the modulation by phospholamban regulated by cAMP-mediated, PKA-activated signaling. The model faithfully predicted the entire range of physiological chronotropic modulation of SANCs by the activation of beta-adrenergic receptors or cholinergic receptors only when experimentally documented changes of sarcolemmal ion channels are combined with a simultaneous increase/decrease in SR Ca(2+) pumping capability. The novel numerical mechanism of GPCR rate modulation is based on numerous complex synergistic interactions between sarcolemmal and intracellular processes via membrane voltage and Ca(2+). Major interactions include changes of diastolic Na(+)/Ca(2+) exchanger current that couple earlier/later diastolic Ca(2+) releases (predicting the experimentally defined LCR period shift) of increased/decreased amplitude (predicting changes in LCR signal mass, i.e., the product of LCR spatial size, amplitude, and number per cycle) to the diastolic depolarization and ultimately to the spontaneous action potential firing rate. Concomitantly, larger/smaller and more/less frequent activation of L-type Ca(2+) current shifts the cellular Ca(2+) balance to support the respective Ca(2+) cycling changes. In conclusion, our model simulations corroborate recent experimental results in rabbit SANCs pointing to a new paradigm for GPCR heart rate modulation by a complex system of dynamically coupled sarcolemmal and intracellular proteins.

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Section: Discussionsupporting

confidence: 87%

Section: Prediction Of Chr Stimulationmentioning

confidence: 99%

A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins

Maltsev

Lakatta

2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Parasympathetic tone is regulated by cholinergic signaling, which affects pacemaker function, enhances pacemaker shifting, slows the HR by altering the hyperpolarization-activated cation current (I f ) and the muscarinic receptor activated K + current (I K,Ach ), and reduces Ca 2+ transients (24)(25)(26). We next examined whether deletion of STIM1 altered the sensitivity of the SAN in response to cholinergic stimulation.…”

Section: Significancementioning

confidence: 99%

STIM1–Ca ²⁺ signaling modulates automaticity of the mouse sinoatrial node

Zhang

Sun

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca 2+ release from internal Ca 2+ stores (Ca 2+ clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca 2+ entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca 2+ stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca 2+ current, a reduction in L-type Ca 2+ current, and enhancing the activities of Na + /Ca 2+ exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca 2+ dynamics in SANCs that links SR Ca 2+ store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN.S inus rhythm of the heart is set by specialized cardiomyocytes located in the sinoatrial node (SAN). These cardiomyocytes (SANCs) lack a resting membrane potential but generate a sinus impulse after spontaneous diastolic depolarization triggers an action potential (AP). Automaticity is achieved in the SANCs by the simultaneous activation of diastolic currents during membrane depolarization and the spontaneous release of Ca 2+ from internal stores (1-3). Several recent studies show that maintenance of sarcoplasmic reticulum (SR) Ca 2+ stores is critically important for SAN automaticity, as is evident from genetic studies involving patients and mice that have leaky SR Ca 2+ stores (4). Mutations in the ryanodine receptor (RYR2) or calsequestrin genes that result in spontaneous Ca 2+ release cause catecholamiergic polymorphic ventricular tachycardia (CPVT) (5, 6). In addition to ventricular arrhythmias, these patients also develop sinus node dysfunction and bradycardia, which frequently requires permanent pacemaker insertion. Computational studies further reinforce the idea that SAN dysfunction results from leaky RYR2-containing Ca 2+ stores (5). These studies emphasize the importance of Ca 2+ signaling in the automaticity of SANCs. Given the emerging role of store-operated Ca 2+ entry (SOCE) in excitable cells, we asked here whether stromal interaction molecule 1 (STIM1) plays a major role in regulating the Ca 2+ signaling and automaticity of SANCs.SANs are structurally and functionally heterogeneous, exhibiting differences in shape and size that correspond to differences in electrophysiological features (7). It is believed that this heterogeneity is required to establish regional zones within the SAN for impulse generation by pacemakers. Under resting conditions, clusters of SANCs serve as the dominant pacemaker ...

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“…Both currents are involved in heart's pacemaker activity and they are regulated by muscarinic receptors [19]. I KACh currents are activated by Gi-coupled M2/M4 muscarinic receptor, where Gi protein directly opens K +1 channels [20].…”

Section: Discussionmentioning

confidence: 99%

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

Labrador-Hernández¹,

Jimenez²,

León³

et al. 2014

WJCD

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Background: Chagas disease is still a public health problem because of the remaining high prevalence, the expansion of the disease into developed countries and the re-emergences by oral transmission outbreaks. Chagas cardiomyopathy evolves as a consequence of an autonomic unbalance where the parasympathetic tone is undermined. Objective: To determine the functionality and expression of muscarinic cholinergic receptors in acute Chagas disease. Methodology: 62 male, 3-week-old Sprague Dawley rats were assayed; 32 were infected with Trypanosoma cruzi trypomastigotes and 30 were healthy controls. Electrocardiographic studies were conducted in the absence or presence of direct muscarinic (oxotremorine and McN-A-343) or indirect agonists (phenylephrine) or antagonist (pirenzepine). Muscarinic M1 and M2 receptor expression was determined by radioligand [ 3 H]-QNB binding assay and immunoblot. Results: Chagasic acute myocarditis was sustained by electrocardiographic signs and histopathological findings. Bradycardia induced by oxotremorine was significantly higher in healthy rats (HR) and the differences were enhanced by CsCl. In the absence of the agonist, CsCl induced a greater bradycardia in chagasic rats (ChR). In HR McN-A-343 induced tachycardia, however it induces bradycardia in the presence of a acetylcholinesterase inhibitor (neostigmine); no effects were observed in ChR. Pirenzepine induced a higher tachycardia in HR. Phenylephrine in the presence of pirenzepine induced a similar bradycardia in both groups, but recovery was faster in ChR. Muscarinic M1 and M2 receptor density was higher in HR. Conclusion: Muscarinic receptor expression and functionality are decreased * Corresponding author. M. Labrador-Hernández et al. 306in the acute Chagas disease that could impact the evolution and prognosis of the disease.

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Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cells

Abstract: We investigated the contribution of the intracellular calcium (Ca transients (Indo-1 fluorescence) were recorded from single isolated rabbit SAN cells, whereas intracellular cAMP content was measured in SAN cell suspensions using a cAMP assay (LANCE Ò

Cited by 49 publications

References 53 publications

A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins

A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins

STIM1–Ca ²⁺ signaling modulates automaticity of the mouse sinoatrial node

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

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Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cells

Abstract: We investigated the contribution of the intracellular calcium (Ca transients (Indo-1 fluorescence) were recorded from single isolated rabbit SAN cells, whereas intracellular cAMP content was measured in SAN cell suspensions using a cAMP assay (LANCE Ò

Cited by 49 publications

References 53 publications

A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins

A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins

STIM1–Ca 2+ signaling modulates automaticity of the mouse sinoatrial node

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

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STIM1–Ca ²⁺ signaling modulates automaticity of the mouse sinoatrial node