کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8474150 | 1550419 | 2015 | 37 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Real-time relationship between PKA biochemical signal network dynamics and increased action potential firing rate in heart pacemaker cells
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کلمات کلیدی
RyRSANCPLBβ-ARpKaCaMKIIPDECa2 +/calmodulin-dependent protein kinase II - Ca2 + / calmodulin وابسته پروتئین کیناز IIAdenylyl cyclases - آدنیلیل سیکلاسISO - ایزوisoproterenol - ایزوپروترنولMembrane - غشاءPhosphorylation - فسفریلاسیونPhosphodiesterase - فسفو دی استرازphospholamban - فسفولامبنComputational modeling - مدل سازی محاسباتیaction potential - پتانسیل عمل protein kinase A - پروتئین کیناز APacemaker - پیس میکر یا ضربان ساز β-Adrenergic receptor - گیرنده β-adrenergicRyanodine receptors - گیرنده های رایانودین
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
cAMP-PKA protein kinase is a key nodal signaling pathway that regulates a wide range of heart pacemaker cell functions. These functions are predicted to be involved in regulation of spontaneous action potential (AP) generation of these cells. Here we investigate if the kinetics and stoichiometry of increase in PKA activity match the increase in AP firing rate in response to β-adrenergic receptor (β-AR) stimulation or phosphodiesterase (PDE) inhibition, that alters the AP firing rate of heart sinoatrial pacemaker cells. In cultured adult rabbit pacemaker cells infected with an adenovirus expressing the FRET sensor AKAR3, the EC50 in response to graded increases in the intensity of β-AR stimulation (by Isoproterenol) the magnitude of the increases in PKA activity and the spontaneous AP firing rate were similar (0.4 ± 0.1 nM vs. 0.6 ± 0.15 nM, respectively). Moreover, the kinetics (t1/2) of the increases in PKA activity and spontaneous AP firing rate in response to β-AR stimulation or PDE inhibition were tightly linked. We characterized the system rate-limiting biochemical reactions by integrating these experimentally derived data into a mechanistic-computational model. Model simulations predicted that phospholamban phosphorylation is a potent target of the increase in PKA activity that links to increase in spontaneous AP firing rate. In summary, the kinetics and stoichiometry of increases in PKA activity in response to a physiological (β-AR stimulation) or pharmacological (PDE inhibitor) stimuli match those of changes in the AP firing rate. Thus Ca2 +-cAMP/PKA-dependent phosphorylation limits the rate and magnitude of increase in spontaneous AP firing rate.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 86, September 2015, Pages 168-178
Journal: Journal of Molecular and Cellular Cardiology - Volume 86, September 2015, Pages 168-178
نویسندگان
Yael Yaniv, Ambhighainath Ganesan, Dongmei Yang, Bruce D. Ziman, Alexey E. Lyashkov, Andre Levchenko, Jin Zhang, Edward G. Lakatta,