Adenylyl cyclase type 6 deletion decreases left ventricular function via impaired calcium handling.

Abstract:

BACKGROUND:Adenylyl cyclases (ACs) are a family of effector molecules for G-protein-coupled receptors. The 2 ACs most abundantly expressed in cardiac myocytes are types 5 (AC5) and 6 (AC6), which have 65% amino acid homology. It has been speculated that coexpression of 2 AC types in cardiac myocytes represents redundancy, but the specific role of AC6 in cardiac physiology and its differences from AC5 remain to be defined. METHODS AND RESULTS:We generated transgenic mice with targeted deletion of AC6. Deletion of AC6 was associated with reduced left ventricular contractile function (P=0.026) and relaxation (P=0.041). The absence of AC6 was associated with a 48% decay in beta-adrenergic receptor-stimulated cAMP production in cardiac myocytes (P=0.003) and reduced protein kinase A activity (P=0.015). In addition, phospholamban phosphorylation was reduced (P=0.015), sarcoplasmic reticulum Ca2+-ATPase activity was impaired (P<0.0001), and cardiac myocytes showed marked abnormalities in calcium transient formation (P=0.001). CONCLUSIONS:The combination of impaired cardiac cAMP generation and calcium handling that result from AC6 deletion underlies abnormalities in left ventricular function. The biochemical and physiological consequences of AC6 deletion reveal it to be an important effector molecule in the adult heart, serving unique biological functions not replicated by AC5.

journal_name

Circulation

journal_title

Circulation

authors

Tang T,Gao MH,Lai NC,Firth AL,Takahashi T,Guo T,Yuan JX,Roth DM,Hammond HK

doi

10.1161/CIRCULATIONAHA.107.730069

subject

Has Abstract

pub_date

2008-01-01 00:00:00

pages

61-9

issue

1

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.107.730069

journal_volume

117

pub_type

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