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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Autores principales:	Yong Li, Tanya A. Baldwin, Yan Wang, Janani Subramaniam, Anibal Garza Carbajal, Cameron S. Brand, Shane R. Cunha, Carmen W. Dessauer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/af877f9b937d4ba8b7fad80085ffdd9a
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spelling	oai:doaj.org-article:af877f9b937d4ba8b7fad80085ffdd9a2021-12-02T15:05:33ZLoss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction10.1038/s41598-017-05816-w2045-2322https://doaj.org/article/af877f9b937d4ba8b7fad80085ffdd9a2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05816-whttps://doaj.org/toc/2045-2322Abstract 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.Yong LiTanya A. BaldwinYan WangJanani SubramaniamAnibal Garza CarbajalCameron S. BrandShane R. CunhaCarmen W. DessauerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	loss of type 9 adenylyl cyclase triggers reduced phosphorylation of hsp20 and diastolic dysfunction
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/af877f9b937d4ba8b7fad80085ffdd9a
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Loss of type 9 adenylyl cyclase triggers reduced phosphorylation of Hsp20 and diastolic dysfunction

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