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


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.
Tang
Tong
T
Department of Medicine, University of California, San Diego, USA.
Gao
Mei Hua
MH
Lai
N Chin
NC
Firth
Amy L
AL
Takahashi
Toshiyuki
T
Guo
Tracy
T
Yuan
Jason X-J
JX
Roth
David M
DM
Hammond
H Kirk
HK
D000262:Adenylyl Cyclases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D003971:Diastole; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D018487:Ventricular Dysfunction, Left
D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D002118:Calcium