Decreased polycystin 2 expression alters calcium-contraction coupling and changes β-adrenergic signaling pathways.

Abstract

Cardiac disorders are the main cause of mortality in autosomal-dominant polycystic kidney disease (ADPKD). However, how mutated polycystins predispose patients with ADPKD to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased levels of polycystin 2 (PC2), a calcium channel that interacts with the ryanodine receptor, on myocardial function. We hypothesize that heterozygous PC2 mice (Pkd2(+/-)) undergo cardiac remodeling as a result of changes in calcium handling, separate from renal complications. We found that Pkd2(+/-) cardiomyocytes have altered calcium handling, independent of desensitized calcium-contraction coupling. Paradoxically, in Pkd2(+/-) mice, protein kinase A (PKA) phosphorylation of phospholamban (PLB) was decreased, whereas PKA phosphorylation of troponin I was increased, explaining the decoupling between calcium signaling and contractility. In silico modeling supported this relationship. Echocardiography measurements showed that Pkd2(+/-) mice have increased left ventricular ejection fraction after stimulation with isoproterenol (ISO), a β-adrenergic receptor (βAR) agonist. Blockers of βAR-1 and βAR-2 inhibited the ISO response in Pkd2(+/-) mice, suggesting that the dephosphorylated state of PLB is primarily by βAR-2 signaling. Importantly, the Pkd2(+/-) mice were normotensive and had no evidence of renal cysts. Our results showed that decreased PC2 levels shifted the βAR pathway balance and changed expression of calcium handling proteins, which resulted in altered cardiac contractility. We propose that PC2 levels in the heart may directly contribute to cardiac remodeling in patients with ADPKD in the absence of renal dysfunction.

• Authors: Ivana Y Kuo, Andrea T Kwaczala, Lily Nguyen, Kerry S Russell, Stuart G Campbell, Barbara E Ehrlich
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 46 Pg. 16604-9 (Nov 18 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25368166 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Agonists
• Adrenergic beta-Antagonists
• Calcium-Binding Proteins
• RNA, Messenger
• Receptors, Adrenergic, beta-1
• Receptors, Adrenergic, beta-2
• Ryanodine Receptor Calcium Release Channel
• TRPP Cation Channels
• Troponin I
• phospholamban
• polycystic kidney disease 2 protein
• ryanodine receptor 2. mouse
• Caffeine
• Isoproterenol

Topics

• Adrenergic beta-Agonists (pharmacology)
• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Blood Pressure (genetics)
• Caffeine (pharmacology)
• Calcium Signaling (drug effects, physiology)
• Calcium-Binding Proteins (metabolism)
• Cardiac Pacing, Artificial
• Excitation Contraction Coupling (drug effects, genetics, physiology)
• Heterozygote
• Isoproterenol (pharmacology)
• Kidney (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (physiology)
• Phosphorylation (drug effects)
• Protein Processing, Post-Translational (drug effects)
• RNA, Messenger (biosynthesis)
• Receptors, Adrenergic, beta-1 (drug effects, physiology)
• Receptors, Adrenergic, beta-2 (drug effects, physiology)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Signal Transduction (physiology)
• TRPP Cation Channels (deficiency, genetics, physiology)
• Troponin I (metabolism)
• Ventricular Remodeling (drug effects, genetics, physiology)