scholarly journals Dual Activation of Phosphodiesterase 3 and 4 Regulates Basal Cardiac Pacemaker Function and Beyond

2021 ◽  
Vol 22 (16) ◽  
pp. 8414
Author(s):  
Tatiana M. Vinogradova ◽  
Edward G. Lakatta
Keyword(s):  
Cardiac Pacemaker ◽  
Adenylyl Cyclases ◽  
Camp Production ◽  
Sa Node ◽  
Phosphodiesterase 3 ◽  
Pacemaker Function ◽  
Dependent Protein ◽  
Beating Rate ◽  
Dual Activation ◽  
High Level

The sinoatrial (SA) node is the physiological pacemaker of the heart, and resting heart rate in humans is a well-known risk factor for cardiovascular disease and mortality. Consequently, the mechanisms of initiating and regulating the normal spontaneous SA node beating rate are of vital importance. Spontaneous firing of the SA node is generated within sinoatrial nodal cells (SANC), which is regulated by the coupled-clock pacemaker system. Normal spontaneous beating of SANC is driven by a high level of cAMP-mediated PKA-dependent protein phosphorylation, which rely on the balance between high basal cAMP production by adenylyl cyclases and high basal cAMP degradation by cyclic nucleotide phosphodiesterases (PDEs). This diverse class of enzymes includes 11 families and PDE3 and PDE4 families dominate in both the SA node and cardiac myocardium, degrading cAMP and, consequently, regulating basal cardiac pacemaker function and excitation-contraction coupling. In this review, we will demonstrate similarities between expression, distribution, and colocalization of various PDE subtypes in SANC and cardiac myocytes of different species, including humans, focusing on PDE3 and PDE4. Here, we will describe specific targets of the coupled-clock pacemaker system modulated by dual PDE3 + PDE4 activation and provide evidence that concurrent activation of PDE3 + PDE4, operating in a synergistic manner, regulates the basal cardiac pacemaker function and provides control over normal spontaneous beating of SANCs through (PDE3 + PDE4)-dependent modulation of local subsarcolemmal Ca2+ releases (LCRs).

scholarly journals CaMKII-dependent phosphorylation regulates basal cardiac pacemaker function via modulation of local Ca2+ releases

2016 ◽  
Vol 311 (3) ◽  
pp. H532-H544 ◽  
Author(s):  
Yue Li ◽  
Syevda Sirenko ◽  
Daniel R. Riordon ◽  
Dongmei Yang ◽  
Harold Spurgeon ◽  
...  
Keyword(s):  
Protein Phosphorylation ◽  
Sinoatrial Node ◽  
Ventricular Myocytes ◽  
Ryanodine Receptors ◽  
Cardiac Pacemaker ◽  
Gradual Change ◽  
Pacemaker Function ◽  
Dependent Protein ◽  
Highly Correlated ◽  
Camkii Activation

Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) due to gradual change of the membrane potential called diastolic depolarization (DD). Spontaneous, submembrane local Ca2+ releases (LCR) from ryanodine receptors (RyR) occur during late DD and activate an inward Na+/Ca2+exchange current to boost the DD rate and fire an action potential (AP). Here we studied the extent of basal Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and the role of basal CaMKII-dependent protein phosphorylation in generation of LCRs and regulation of normal automaticity of intact rabbit SANC. The basal level of activated (autophosphorylated) CaMKII in rabbit SANC surpassed that in ventricular myocytes (VM) by approximately twofold, and this was accompanied by high basal level of protein phosphorylation. Specifically, phosphorylation of phospholamban (PLB) at the CaMKII-dependent Thr17 site was approximately threefold greater in SANC compared with VM, and RyR phosphorylation at CaMKII-dependent Ser2815 site was ∼10-fold greater in the SA node, compared with that in ventricle. CaMKII inhibition reduced phosphorylation of PLB and RyR, decreased LCR size, increased LCR periods (time from AP-induced Ca2+ transient to subsequent LCR), and suppressed spontaneous SANC firing. Graded changes in CaMKII-dependent phosphorylation (indexed by PLB phosphorylation at the Thr17site) produced by CaMKII inhibition, β-AR stimulation or phosphodiesterase inhibition were highly correlated with changes in SR Ca2+ replenishment times and LCR periods and concomitant changes in spontaneous SANC cycle lengths ( R2 = 0.96). Thus high basal CaMKII activation modifies the phosphorylation state of Ca2+ cycling proteins PLB, RyR, L-type Ca2+ channels (and likely others), adjusting LCR period and characteristics, and ultimately regulates both normal and reserve cardiac pacemaker function.

P2558PDE4 regulates cardiac pacemaker function

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D Mika ◽  
A M Gomez ◽  
R Fischmeister ◽  
G Vandecasteele
Keyword(s):  
Cardiac Pacemaker ◽  
Hydrolytic Activity ◽  
Pde4 Inhibitor ◽  
Pacemaker Activity ◽  
Ventricular Cells ◽  
Pacemaker Function ◽  
S 100 ◽  
Beating Rate ◽  
Respective Contribution

Abstract Background Numerous epidemiological and clinical studies have revealed a positive correlation between heart rate (HR) and cardiovascular morbimortality. The autonomic nervous system is the major extracardiac determinant of HR. During sympathetic stimulation, the activation of β-adrenergic receptors (βAR) induces an increase in cAMP levels, leading to positive chronotropic effect. Among the 5 cardiac cAMP-PDE families, PDE4 is critical for controlling excitation-contraction coupling (ECC) during βAR stimulation in atrial and ventricular cells. PDE4 may also be important for automaticity. 3 genes encode for PDE4s: pde4a, pde4b, pde4d. Their respective contribution to the regulation of pacemaker activity remains ill-defined. Purpose Define the role of PDE4 isoforms in the regulation of cardiac pacemaker activity Methods Total PDE activity was determined in mouse sinoatrial node (SAN) tissue as the cAMP-hydrolytic activity measured in the absence of PDE inhibitor and the fraction corresponding to PDE4 activity was assessed by including the PDE4 inhibitor Ro-20-1724. The in vitro pacemaker activity was assessed by measuring spontaneous Ca2+ transients in Fluo4-loaded-SAN tissue. Images were obtained using confocal microscopy. Results Ro-20-1724 increased beating rate of intact SAN and increased PKA-phosphorylation of key ECC actors (ryanodine receptor, phospholamban and contractile proteins). PDE4 activity was found to account for 60% of the total cAMP-PDE activity in SAN (n=3 independent experiments). PDE4A, PDE4B and PDE4D isoforms were found to be expressed in mouse SAN (n=5 independent experiments). In PDE4D-, but not in PDE4B-deficient mice, Ca2+ homeostasis was altered in control conditions (ctrl) and after βAR stimulation with isoprenaline (iso). Indeed, ablation of PDE4D induced decreased beating rate (ctrl: 1.00±0.08 s–1 vs 1.57±0.05 s–1; iso: 1.71±0.17 s–1 vs 2.39±0.08 s–1, p<0.0001) and increased Ca2+ spark frequency (ctrl: 15.9±5.2 sparks/s/100 μm vs 1.9±0.4 sparks/s/100 μm; iso: 22.9±7.1 sparks/s/100 μm vs 0.6±0.2 sparks/s/100 μm, p<0.0001) (Figure). Calcium Homeostasis in SAN cells Conclusion PDE4 controls pacemaker function in mice and PDE4D ablation strongly perturbs normal SAN activity. Acknowledgement/Funding ANR, Fondation Lefoulon Delalande, CORDDIM

Normal spontaneous firing of cardiac pacemaker cells is regulated by basal pkc delta activation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Vinogradova ◽  
K Tarasov ◽  
D Riordon ◽  
Y Tarasova ◽  
E Lakatta
Keyword(s):  
Protein Kinase ◽  
Cycle Length ◽  
Cardiac Pacemaker ◽  
Funding Source ◽  
Spontaneous Firing ◽  
Pacemaker Cells ◽  
Patch Clamp Technique ◽  
Sa Node ◽  
Pkc Delta ◽  
Pkc Isoforms

Abstract   The spontaneous beating rate of rabbit sinoatrial node cells (SANC) is regulated by local subsarcolemmal calcium releases (LCRs) from sarcoplasmic reticulum (SR). LCRs appear during diastolic depolarization (DD) and activate an inward sodium/calcium exchange current which increases DD rate and thus accelerates spontaneous SANC firing. High basal level of protein kinase A and calcium/calmodulin-dependent protein kinase II phosphorylation are required to sustain basal LCRs and normal spontaneous SANC firing. Recently we discovered that basal PKC activation is also obligatory for cardiac pacemaker function: inhibition of PKC activity by broad spectrum PKC inhibitors Bis I or calphostin C markedly suppressed SR calcium cycling and decreased or abolished spontaneous beating of freshly isolated rabbit SANC. Here we studied which PKC isoforms mediate PKC-dependent effects on cardiac pacemaker cell automaticity. The PKC superfamily consists of 3 major subgroups: conventional, novel and atypical. All PKC isoforms were detected at the RNA level (RT-qPCR) in the rabbit SA node and ventricle, and expression levels were comparable in both tissues. Expression of PKCβ, however, was markedly higher in the rabbit SA node, compared to other PKC isoenzymes in either tissue. We verified expression of conventional PKC (α, β) and novel PKC-delta at the protein level in SANC and ventricular myocytes (VM). Western blot confirmed RNA results, showing a 6-fold higher PKCβ protein abundance in SANC compared to VM. Expression of PKCα protein was similar in both cell types, while PKC-delta protein was more abundant in VM. To study whether PKCβ regulates spontaneous beating of SANC we employed selective inhibitor of conventional (α, β, gamma) PKC isoforms Go6976 (10 μmol/L), which had no effects on either LCR characteristics (confocal microscopy, calcium indicator Fluo-3AM) or spontaneous beating of freshly isolated rabbit SANC (perforated patch-clamp technique). Because selective PKC-delta inhibitors are not available, we explored effects of PKC-delta inhibition comparing effects of Go6976 (the inhibitor of conventional PKCs) and Go6983, which inhibits conventional PKCs and PKC-delta. In contrast to Go6976, Go6983 (5 μmol/L) markedly decreased the LCR size (from 7.1±0.4 to 4.5±0.3 μm) and number per each spontaneous cycle (from 1.3±0.1 to 0.8±0.1). It also markedly increased the LCR period (time from the prior AP-induced calcium transient to the subsequent LCR) which was paralleled by an increase in the spontaneous SANC cycle length. Rottlerin, another PKC-delta inhibitor, produced similar effects on LCR characteristics, and markedly and time-dependently decreased DD rate, leading to an increase in the spontaneous cycle length, and finally abrogated the spontaneous SANC firing. Thus, our data indicate that basal activity of PKC-delta, but not that of PKCβ, is essential for generation of LCRs and normal spontaneous firing of cardiac pacemaker cells. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Intramural Research Program, National Institute on Aging, National Institute of Health, USA

Functional changes in adenylyl cyclases and associated decreases in relaxation responses in mesenteric arteries from diabetic rats

2005 ◽  
Vol 289 (5) ◽  
pp. H2234-H2243 ◽  
Author(s):  
Takayuki Matsumoto ◽  
Kentaro Wakabayashi ◽  
Tsuneo Kobayashi ◽  
Katsuo Kamata
Keyword(s):  
Mesenteric Artery ◽  
Diabetic Rats ◽  
Functional Change ◽  
Water Soluble ◽  
Mesenteric Arteries ◽  
Diabetic Rat ◽  
Adenylyl Cyclases ◽  
Camp Production ◽  
Functional Changes ◽  
Rat Mesenteric Artery

To assess the functional change in adenylyl cyclases (AC) associated with the diabetic state, we investigated AC-mediated relaxations and cAMP production in mesenteric arteries from rats with streptozotocin (STZ)-induced diabetes. The relaxations induced by the water-soluble forskolin (FSK) analog NKH477, which is a putative AC5 activator, but not by the β-adrenoceptor agonist isoproterenol (Iso) and the AC activator FSK, were reduced in intact diabetic mesenteric artery. In diabetic rats, however, Iso-, FSK-, and NKH477-induced relaxations were attenuated in the presence of inhibitors of nitric oxide synthase and cyclooxygenase. To exclude the influence of phosphodiesterase (PDE), we also examined the relaxations induced by several AC activators in the presence of 3-isobutyl-1-methylxanthine (IBMX; a PDE inhibitor). Under these conditions, the relaxation induced by Iso was greatly impaired in STZ-diabetic rats. This Iso-induced relaxation was significantly attenuated by pretreatment with SQ-22536, an AC inhibitor, in mesenteric rings from age-matched controls but not in those from STZ-diabetic rats. Under the same conditions, the relaxations induced by FSK or NKH477 were impaired in STZ-diabetic rats. Neither FSK- nor A-23187 (a Ca2+ ionophore)-induced cAMP production was significantly different between diabetics and controls. However, cAMP production induced by Iso or NKH477 was significantly impaired in diabetic mesenteric arteries. Expression of mRNAs and proteins for AC5/6 was lower in diabetic mesenteric arteries than in controls. These results suggest that AC-mediated relaxation is impaired in the STZ-diabetic rat mesenteric artery, perhaps reflecting a reduction in AC5/6 activity.

Effect of Chest Wall Stimulation on Cardiac Pacemaker Function

1970 ◽  
Vol 260 (5) ◽  
pp. 285-298 ◽  
Author(s):  
P Samel ◽  
S Z Abbas ◽  
F J Hildner ◽  
R P Javier ◽  
B Befeler ◽  
...  
Keyword(s):  
Chest Wall ◽  
Cardiac Pacemaker ◽  
Pacemaker Function

scholarly journals Glucose and GLP-1 Stimulate cAMP Production via Distinct Adenylyl Cyclases in INS-1E Insulinoma Cells

2008 ◽  
Vol 132 (3) ◽  
pp. 329-338 ◽  
Author(s):  
Lavoisier S. Ramos ◽  
Jonathan Hale Zippin ◽  
Margarita Kamenetsky ◽  
Jochen Buck ◽  
Lonny R. Levin
Keyword(s):  
Calcium Influx ◽  
Cellular Responses ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Cascades ◽  
Adenylyl Cyclases ◽  
Camp Production ◽  
Β Cells ◽  
Soluble Adenylyl Cyclase ◽  
Mitogen Activated Protein ◽  
Insulinoma Cells

In β cells, both glucose and hormones, such as GLP-1, stimulate production of the second messenger cAMP, but glucose and GLP-1 elicit distinct cellular responses. We now show in INS-1E insulinoma cells that glucose and GLP-1 produce cAMP with distinct kinetics via different adenylyl cyclases. GLP-1 induces a rapid cAMP signal mediated by G protein–responsive transmembrane adenylyl cyclases (tmAC). In contrast, glucose elicits a delayed cAMP rise mediated by bicarbonate, calcium, and ATP-sensitive soluble adenylyl cyclase (sAC). This glucose-induced, sAC-dependent cAMP rise is dependent upon calcium influx and is responsible for the glucose-induced activation of the mitogen-activated protein kinase (ERK1/2) pathway. These results demonstrate that sAC-generated and tmAC-generated cAMP define distinct signaling cascades.

cAMP inhibits IP3-dependent Ca2+ release by preferential activation of cGMP-primed PKG

2001 ◽  
Vol 281 (5) ◽  
pp. G1238-G1245 ◽  
Author(s):  
Karnam S. Murthy
Keyword(s):  
Muscle Contraction ◽  
Muscle Cells ◽  
Dependent Protein Kinase ◽  
Permeabilized Cells ◽  
Phosphodiesterase 3 ◽  
Low Concentrations ◽  
Intact Muscle ◽  
Dependent Protein ◽  
Camp And Cgmp ◽  
Permeabilized Muscle

The singular effects and interplay of cAMP- and cGMP-dependent protein kinase (PKA and PKG) on Ca2+ mobilization were examined in dispersed smooth muscle cells. In permeabilized muscle cells, exogenous cAMP and cGMP inhibited inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release and muscle contraction via PKA and PKG, respectively. A combination of cAMP and cGMP caused synergistic inhibition that was exclusively mediated by PKG and attenuated by PKA. In intact muscle cells, low concentrations (10 nM) of isoproterenol and sodium nitroprusside (SNP) inhibited agonist-induced, IP3-dependent Ca2+ release and muscle contraction via PKA and PKG, respectively. A combination of isoproterenol and SNP increased PKA and PKG activities: the increase in PKA activity reflected inhibition of phosphodiesterase 3 activity by cGMP, whereas the increase in PKG activity reflected activation of cGMP-primed PKG by cAMP. Inhibition of Ca2+ release and muscle contraction by the combination of isoproterenol and SNP was preferentially mediated by PKG. In light of studies showing that PKG phosphorylates the IP3 receptor in intact and permeabilized muscle cells, whereas PKA phosphorylates the receptor in permeabilized cells only, the results imply that inhibition of IP3-induced Ca2+ release is mediated exclusively by PKG. The effect of PKA on agonist-induced Ca2+ release probably reflects inhibition of IP3 formation.

Cardiac pacemaker function

JAMA ◽  
1972 ◽  
Vol 222 (11) ◽  
pp. 1379-1382 ◽  
Author(s):  
R. S. Pennock
Keyword(s):  
Cardiac Pacemaker ◽  
Pacemaker Function
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