Targeted inhibition of Ca2+/calmodulin-dependent protein kinase II in cardiac longitudinal sarcoplasmic reticulum results in decreased phospholamban phosphorylation at threonine 17
| Autor: | John R. Dedman, Marcia A. Kaetzel, John N. Lorenz, Thomas D. Reed, Yong Ji, Bailing Li |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Cardiac function curve
Threonine medicine.medical_specialty Heart Diseases Biology Biochemistry Ryanodine receptor 2 Contractility Mice Internal medicine medicine Animals Phosphorylation Molecular Biology Kinase Endoplasmic reticulum Myocardium Calcium-Binding Proteins Cell Biology musculoskeletal system Phospholamban Sarcoplasmic Reticulum Endocrinology Calcium-Calmodulin-Dependent Protein Kinases cardiovascular system Longitudinal sarcoplasmic reticulum Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 278(27) |
| ISSN: | 0021-9258 |
| Popis: | To investigate the role of Ca2+/calmodulin-dependent kinase II in cardiac sarcoplasmic reticulum function, transgenic mice were designed and generated to target the expression of a Ca2+/calmodulin-dependent kinase II inhibitory peptide in cardiac longitudinal sarcoplasmic reticulum using a truncated phospholamban transmembrane domain. The expressed inhibitory peptide was highly concentrated in cardiac sarcoplasmic reticulum. This resulted in a 59.7 and 73.6% decrease in phospholamban phosphorylation at threonine 17 under basal and beta-adrenergic stimulated conditions without changing phospholamban phosphorylation at serine 16. Sarcoplasmic reticulum Ca2+ uptake assays showed that the Vmax was decreased by approximately 30% although the apparent affinity for Ca2+ was unchanged in heterozygous hearts. The in vivo measurement of cardiac function showed no significant reductions in positive and negative dP/dt, but a moderate 18% decrease in dP/dt40, indicative of isovolumic contractility, and a 26.1% increase in the time constant of relaxation (tau) under basal conditions. The changes in these parameters indicate a moderate cardiac dysfunction in transgenic mice. Although the 3 and 4-month-old transgenic mice displayed no overt signs of cardiac disease, when stressed by gestation and parturition, the 7-month-old female mice develop dilated heart failure, suggesting the important role of Ca2+/calmodulin-dependent kinase II pathway in the development of cardiac disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|