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Attenuated β-adrenergic response in calcium/calmodulin-dependent protein kinase IV-knockout mice
Manabu Murakami1, Agnieszka M Murakami1, Yasushi Matsuzaki2
1Department of Pharmacology, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan.
Abstract:
In the present study, we examined the importance of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) in the regulation of cardiac function using genetically modified CaMKIV-null mice. RT-PCR analysis revealed decreased expression of voltage-dependent calcium channels in the cardiac myocytes of CaMKIV-null mice compared with wild-type mice. CaMKIV-null mice showed shortened QT time on electrocardiograms. Pharmacological analysis revealed decreased responsiveness to the β-adrenergic blocker propranolol in CaMKIV-null mice, whereas the plasma norepinephrine level was not affected. CaMKIV-null mice showed decreased baroreflex on electrocardiograms. Heart rate variability analysis showed unstable R-R intervals, a decreased low frequency power/high frequency power (LF/HF) ratio, and increased standard deviation of the normal to normal R-R intervals (SDNN) in CaMKIV-null mice, suggesting decreased responsiveness to β-adrenergic stimulation in CaMKIV-null mice. Atrial contraction analysis and cardiac action potential recording showed a decreased response to the β-adrenoceptor agonist isoproterenol in CaMKIV-null mice. Furthermore, fluorescence imaging in a CRE-hrGFP assay revealed a decreased response to isoproterenol in CaMKIV-null cardiac myocytes. Taken together, our data strongly suggest a significant effect of CaMKIV gene ablation on cardiac β-adrenergic signal transduction.
Insights
Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) gene ablation impairs cardiac function. CaMKIV-null mice exhibit reduced cardiac beta-adrenergic signaling, impacting heart rate variability and electrical activity.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) plays a role in cellular signaling.
- Understanding CaMKIV's role in cardiac function is crucial for cardiovascular research.
Purpose of the Study:
- To investigate the function of CaMKIV in regulating cardiac function.
- To determine the impact of CaMKIV gene ablation on cardiac beta-adrenergic signaling.
Main Methods:
- Utilized CaMKIV-null mice for genetic modification studies.
- Performed RT-PCR, electrocardiography, pharmacological challenges, heart rate variability analysis, atrial contraction assays, cardiac action potential recordings, and fluorescence imaging.
Main Results:
- CaMKIV-null mice displayed reduced voltage-dependent calcium channel expression.
- Shortened QT time and decreased baroreflex sensitivity were observed.
- Reduced responsiveness to beta-adrenergic stimulation (propranolol and isoproterenol) was evident.
- Heart rate variability analysis indicated impaired autonomic regulation.
Conclusions:
- CaMKIV gene ablation significantly affects cardiac beta-adrenergic signal transduction.
- CaMKIV is essential for normal cardiac electrophysiology and response to adrenergic stimuli.
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