Role of inositol 1,4,5-trisphosphate receptors in alpha1-adrenergic receptor-induced cardiomyocyte hypertrophy.

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.

• 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)

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

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