Published online before print July 17, 2003, doi: 10.1161/01.RES.0000086986.35568.63
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 14, 2003
Revised on July 8, 2003
Accepted on July 8, 2003
Type 5 Adenylyl Cyclase Disruption Alters Not Only Sympathetic But Also Parasympathetic and Calcium-Mediated Cardiac Regulation
Satoshi Okumura ;
From the Cardiovascular Research Institute, Department of Cell Biology & Molecular Medicine and Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ.
* To whom correspondence should be addressed. E-mail: vatnersf{at}umdnj.edu.
In a genetically engineered mouse line with disruption of type 5 adenylyl cyclase (AC5-/-), a major cardiac isoform, there was no compensatory increase in other isoforms of AC in the heart. Both basal and isoproterenol (ISO)-stimulated AC activities were decreased by 30% to 40% in cardiac membranes. The reduced AC activity did not affect cardiac function (left ventricular ejection fraction [LVEF]) at baseline. However, increases in LVEF after ISO were significantly attenuated in AC5-/- (P<0.05, n=11). Paradoxically, conscious AC5-/- mice had a higher heart rate compared with wild-type (WT) mice (613±8 versus 523±11 bpm, P<0.01, n=14 to 15). Muscarinic agonists decreased AC activity, LVEF, and heart rate more in WT than in AC5-/-. In addition, baroreflex-mediated, ie, neuronally regulated, bradycardia after phenylephrine was also attenuated in AC5-/-. The carbachol-activated outward potassium current (at -40 mV) normalized to cell capacitance in AC5-/- (2.6±0.4 pA/pF, n=16) was similar to WT (2.9±0.3 pA/pF, n=27), but calcium (Ca2+)-mediated inhibition of AC activity and Ca2+ channel function were diminished in AC5-/-. Thus, AC5-/- attenuates sympathetic responsiveness and also impairs parasympathetic and Ca2+-mediated regulation of the heart, indicating that those actions are not only regulated at the level of the receptor and G-protein but also at the level of type 5 AC.
Key words:
-adrenergic receptors •
muscarinic receptors •
calcium channels •
knockout •
adenylyl cyclase isoforms
This article has been cited by other articles:
 |
|
 |
|
  S. Okumura, T. Tsunematsu, Y. Bai, Q. Jiao, S. Ono, S. Suzuki, R. Kurotani, M. Sato, S. Minamisawa, S. Umemura, et al. Type 5 adenylyl cyclase plays a major role in stabilizing heart rate in response to microgravity induced by parabolic flight J Appl Physiol, July 1, 2008; 105(1): 173 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tang, M. H. Gao, N. C. Lai, A. L. Firth, T. Takahashi, T. Guo, J. X.-J. Yuan, D. M. Roth, and H. K. Hammond Adenylyl Cyclase Type 6 Deletion Decreases Left Ventricular Function via Impaired Calcium Handling Circulation, January 1, 2008; 117(1): 61 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Chester and V. J. Watts Adenylyl Cyclase 5: A New Clue in the Search for the "Fountain of Youth"? Sci. Signal., November 20, 2007; 2007(413): pe64 - pe64. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Okumura, D. E. Vatner, R. Kurotani, Y. Bai, S. Gao, Z. Yuan, K. Iwatsubo, C. Ulucan, J.-i. Kawabe, K. Ghosh, et al. Disruption of Type 5 Adenylyl Cyclase Enhances Desensitization of Cyclic Adenosine Monophosphate Signal and Increases Akt Signal With Chronic Catecholamine Stress Circulation, October 16, 2007; 116(16): 1776 - 1783. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Willoughby and D. M. F. Cooper Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains Physiol Rev, July 1, 2007; 87(3): 965 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Rottlaender, J. Matthes, S. F. Vatner, R. Seifert, and S. Herzig Functional Adenylyl Cyclase Inhibition in Murine Cardiomyocytes by 2'(3')-O-(N-Methylanthraniloyl)-Guanosine 5'-[{gamma}-Thio]triphosphate J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 608 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Fischmeister, L. R.V. Castro, A. Abi-Gerges, F. Rochais, J. Jurevicius, J. Leroy, and G. Vandecasteele Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases Circ. Res., October 13, 2006; 99(8): 816 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Iwatsubo, S. Minamisawa, T. Tsunematsu, M. Nakagome, Y. Toya, J. E. Tomlinson, S. Umemura, R. M. Scarborough, D. E. Levy, and Y. Ishikawa Direct Inhibition of Type 5 Adenylyl Cyclase Prevents Myocardial Apoptosis without Functional Deterioration J. Biol. Chem., September 24, 2004; 279(39): 40938 - 40945. [Abstract] [Full Text] [PDF]
|
|