title: 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.affiliation: Departments of Pharmacology.
authors.forename: Ivana Y
authors.initials: IY
authors.lastname: Kuo
authors.affiliation: Biomedical Engineering.
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Kwaczala
authors.affiliation: Departments of Pharmacology.
authors.forename: Lily
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Cardiology, and.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.affiliation: Biomedical Engineering, Cellular and Molecular Physiology, Yale University, New Haven, CT 06520.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Campbell
authors.affiliation: Departments of Pharmacology, Cellular and Molecular Physiology, Yale University, New Haven, CT 06520 barbara.ehrlich@yale.edu.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Ehrlich
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D002110:Caffeine / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D056966:Excitation Contraction Coupling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050396:TRPP Cation Channels / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D019210:Troponin I / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000099211:Phospholamban
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002110:Caffeine; D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D019837:Ryanodine Receptor Calcium Release Channel; D050396:TRPP Cation Channels; D019210:Troponin I; D000099211:Phospholamban; C000592748:ryanodine receptor 2. mouse
keywords: calcium signaling; excitation contraction coupling; β-adrenergic receptor blocker