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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Boheler, Kenneth R. Lyashkov, Alexey E. Mitsak, Megan Younes, Antoine Van Eyk, Jennifer Graham, David Volkova, Maria V. Ruknudin, Abdul M. Li, Yue Lakatta, Edward G. Sheydina, Anna Vinogradova, Tatiana M. Lukyanenko, Yevgeniya O. |
| Description | Author Affiliation: Younes A ( Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, Intramural Research Program, NIH, Baltimore, MD 21224, USA.) |
| Abstract | Spontaneous, rhythmic subsarcolemmal local Ca(2+) releases driven by cAMP-mediated, protein kinase A (PKA)-dependent phosphorylation are crucial for normal pacemaker function of sinoatrial nodal cells (SANC). Because local Ca(2+) releases occur beneath the cell surface membrane, near to where adenylyl cyclases (ACs) reside, we hypothesized that the dual Ca(2+) and cAMP/PKA regulatory components of automaticity are coupled via Ca(2+) activation of AC activity within membrane microdomains. Here we show by quantitative reverse transcriptase PCR that SANC express Ca(2+)-activated AC isoforms 1 and 8, in addition to AC type 2, 5, and 6 transcripts. Immunolabeling of cell fractions, isolated by sucrose gradient ultracentrifugation, confirmed that ACs localize to membrane lipid microdomains. AC activity within these lipid microdomains is activated by Ca(2+) over the entire physiological Ca(2+) range. In intact SANC, the high basal AC activity produces a high level of cAMP that is further elevated by phosphodiesterase inhibition. cAMP and cAMP-mediated PKA-dependent activation of ion channels and Ca(2+) cycling proteins drive sarcoplasmic reticulum Ca(2+) releases, which, in turn, activate ACs. This feed forward 'fail safe' system, kept in check by a high basal phosphodiesterase activity, is central to the generation of normal rhythmic, spontaneous action potentials by pacemaker cells. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 21 |
| Volume Number | 283 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2008-05-23 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adenylate Cyclase Metabolism Calcium Pharmacology Membrane Lipids Membrane Microdomains Enzymology Sinoatrial Node Cytology Genetics Animals Cyclic AMP Cyclic AMP-Dependent Protein Kinases Enzyme Activation Gene Expression Regulation Isoenzymes Drug Effects RNA, Messenger Rabbits Research Support, N.I.H., Intramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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