Published Online
on December 10, 2007

A more recent version of this article appeared on January 1, 2008

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Submitted on July 27, 2007
Accepted on October 26, 2007

Adenylyl Cyclase Type 6 Deletion Decreases Left Ventricular Function via Impaired Calcium Handling

Tong Tang PhD, Mei Hua Gao PhD, N. Chin Lai PhD, Amy L. Firth PhD, Toshiyuki Takahashi MD, PhD, Tracy Guo BS, Jason X.-J. Yuan MD, PhD, David M. Roth PhD, MD, and H. Kirk Hammond MD^*

From the Departments of Medicine (T. Tang, M.H.G., N.C.L., A.L.F., T. Takahashi, T.G., J.X.-J.Y., H.K.H.) and Anesthesiology (D.M.R.), University of California, San Diego, and VA San Diego Healthcare System (T. Tang, M.H.G., N.C.L., D.M.R., H.K.H.), San Diego, Calif.

^* To whom correspondence should be addressed. E-mail: khammond{at}ucsd.edu.

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 -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.

Key words: calcium • knockout mice • heart contractility • receptors, adrenergic, beta

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