Abstract | AIM: Intracellular Ca2+ plays pivotal roles in diverse cellular functions, including gene transcription that underlies cardiac remodeling during stress responses. However, the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the mediation of cardiac intracellular Ca2+ and hypertrophic growth remains elusive. Prior work with neonatal rat ventricular myocytes suggests that activation of IP3Rs may be linked to a1 adrenergic receptor (alpha1AR) increased stereotyped Ca2+ spark occurrence and global Ca2+ oscillations. Thus, we hypothesized that Ca2+ release through IP3Rs was necessary for alpha1AR-stimulated cardiac hypertrophy. METHODS: We used myoinositol 1,4,5-trisphosphate hexakis (butyryloxymethyl) ester (IP3BM), a membrane-permeant ester of IP3, to activate IP3Rs directly, and Fluo 4/AM to measure intracellular Ca2+ signaling. RESULTS: IP3BM (10 micromol x L(-1)) mimicked the effects of phenylephrine, a selective agonist of alpha1AR, in increments in local Ca2+ spark release (especially in the perinuclear area) and global Ca2+ transient frequencies. More importantly, IP3R inhibitors, 2-aminoethoxydiphenyl borate and Xestospongin C, abolished the IP3BM-induced Ca2+ responses, and significantly suppressed alpha1AR-induced cardiomyocyte hypertrophy assayed by cell size, [3H] leucine incorporation and atrial natriuretic factor gene expression, during sustained (48 h) phenylephrine stimulation. CONCLUSION: These results, therefore, provide cellular mechanisms that link IP3R signaling to alpha1AR-stimulated gene expression and cardiomyocyte hypertrophy.
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Authors | Da-li Luo, Jian Gao, Xiao-mei Lan, Gang Wang, Sheng Wei, Rui-ping Xiao, Qi-de Han |
Journal | Acta pharmacologica Sinica
(Acta Pharmacol Sin)
Vol. 27
Issue 7
Pg. 895-900
(Jul 2006)
ISSN: 1671-4083 [Print] United States |
PMID | 16787574
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adrenergic alpha-1 Receptor Agonists
- Boron Compounds
- Inositol 1,4,5-Trisphosphate Receptors
- Macrocyclic Compounds
- Oxazoles
- RNA, Messenger
- xestospongin C
- Phenylephrine
- Atrial Natriuretic Factor
- 2-aminoethoxydiphenyl borate
- Leucine
- Calcium
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Topics |
- Adrenergic alpha-1 Receptor Agonists
- Animals
- Animals, Newborn
- Atrial Natriuretic Factor
(biosynthesis, genetics)
- Boron Compounds
(pharmacology)
- Calcium
(metabolism)
- Calcium Signaling
(drug effects)
- Cells, Cultured
- Heart Ventricles
- Hypertrophy
(chemically induced)
- Inositol 1,4,5-Trisphosphate Receptors
(physiology)
- Leucine
(metabolism)
- Macrocyclic Compounds
(pharmacology)
- Myocytes, Cardiac
(pathology)
- Oxazoles
(pharmacology)
- Phenylephrine
(pharmacology)
- RNA, Messenger
(biosynthesis, genetics)
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
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