Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction
Abstract Adenylyl cyclase type 9 (AC9) is found tightly associated with the scaffolding protein Yotiao and the IKs ion channel in heart. But apart from potential IKs regulation, physiological roles for AC9 are unknown. We show that loss of AC9 in mice reduces less than 3% of total AC activity in hea...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-05816-w |
| _version_ | 1818835111991312384 |
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| author | Yong Li Tanya A. Baldwin Yan Wang Janani Subramaniam Anibal Garza Carbajal Cameron S. Brand Shane R. Cunha Carmen W. Dessauer |
| author_facet | Yong Li Tanya A. Baldwin Yan Wang Janani Subramaniam Anibal Garza Carbajal Cameron S. Brand Shane R. Cunha Carmen W. Dessauer |
| author_sort | Yong Li |
| collection | DOAJ |
| description | Abstract Adenylyl cyclase type 9 (AC9) is found tightly associated with the scaffolding protein Yotiao and the IKs ion channel in heart. But apart from potential IKs regulation, physiological roles for AC9 are unknown. We show that loss of AC9 in mice reduces less than 3% of total AC activity in heart but eliminates Yotiao-associated AC activity. AC9−/− mice exhibit no structural abnormalities but show a significant bradycardia, consistent with AC9 expression in sinoatrial node. Global changes in PKA phosphorylation patterns are not altered in AC9−/− heart, however, basal phosphorylation of heat shock protein 20 (Hsp20) is significantly decreased. Hsp20 binds AC9 in a Yotiao-independent manner and deletion of AC9 decreases Hsp20-associated AC activity in heart. In addition, expression of catalytically inactive AC9 in neonatal cardiomyocytes decreases isoproterenol-stimulated Hsp20 phosphorylation, consistent with an AC9-Hsp20 complex. Phosphorylation of Hsp20 occurs largely in ventricles and is vital for the cardioprotective effects of Hsp20. Decreased Hsp20 phosphorylation suggests a potential baseline ventricular defect for AC9−/−. Doppler echocardiography of AC9−/− displays a decrease in the early ventricular filling velocity and ventricular filling ratio (E/A), indicative of grade 1 diastolic dysfunction and emphasizing the importance of local cAMP production in the context of macromolecular complexes. |
| first_indexed | 2024-12-19T02:45:32Z |
| format | Article |
| id | doaj.art-af877f9b937d4ba8b7fad80085ffdd9a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T02:45:32Z |
| publishDate | 2017-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-af877f9b937d4ba8b7fad80085ffdd9a2022-12-21T20:38:55ZengNature PortfolioScientific Reports2045-23222017-07-017111110.1038/s41598-017-05816-wLoss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunctionYong Li0Tanya A. Baldwin1Yan Wang2Janani Subramaniam3Anibal Garza Carbajal4Cameron S. Brand5Shane R. Cunha6Carmen W. Dessauer7Dept. Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterDept. Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterDept. Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterDept. Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterDept. Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterDept. Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterDept. Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterDept. Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science CenterAbstract Adenylyl cyclase type 9 (AC9) is found tightly associated with the scaffolding protein Yotiao and the IKs ion channel in heart. But apart from potential IKs regulation, physiological roles for AC9 are unknown. We show that loss of AC9 in mice reduces less than 3% of total AC activity in heart but eliminates Yotiao-associated AC activity. AC9−/− mice exhibit no structural abnormalities but show a significant bradycardia, consistent with AC9 expression in sinoatrial node. Global changes in PKA phosphorylation patterns are not altered in AC9−/− heart, however, basal phosphorylation of heat shock protein 20 (Hsp20) is significantly decreased. Hsp20 binds AC9 in a Yotiao-independent manner and deletion of AC9 decreases Hsp20-associated AC activity in heart. In addition, expression of catalytically inactive AC9 in neonatal cardiomyocytes decreases isoproterenol-stimulated Hsp20 phosphorylation, consistent with an AC9-Hsp20 complex. Phosphorylation of Hsp20 occurs largely in ventricles and is vital for the cardioprotective effects of Hsp20. Decreased Hsp20 phosphorylation suggests a potential baseline ventricular defect for AC9−/−. Doppler echocardiography of AC9−/− displays a decrease in the early ventricular filling velocity and ventricular filling ratio (E/A), indicative of grade 1 diastolic dysfunction and emphasizing the importance of local cAMP production in the context of macromolecular complexes.https://doi.org/10.1038/s41598-017-05816-w |
| spellingShingle | Yong Li Tanya A. Baldwin Yan Wang Janani Subramaniam Anibal Garza Carbajal Cameron S. Brand Shane R. Cunha Carmen W. Dessauer Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction Scientific Reports |
| title | Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction |
| title_full | Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction |
| title_fullStr | Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction |
| title_full_unstemmed | Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction |
| title_short | Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction |
| title_sort | loss of type 9 adenylyl cyclase triggers reduced phosphorylation of hsp20 and diastolic dysfunction |
| url | https://doi.org/10.1038/s41598-017-05816-w |
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