• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


The IP3 receptor regulates cardiac hypertrophy in response to select stimuli.

RATIONALE: Inositol 1,4,5-trisphosphate (IP(3)) is a second messenger that regulates intracellular Ca(2+) release through IP(3) receptors located in the sarco(endo)plasmic reticulum of cardiac myocytes. Many prohypertrophic G protein-coupled receptor (GPCR) signaling events lead to IP(3) liberation, although its importance in transducing the hypertrophic response has not been established in vivo. OBJECTIVE: Here, we generated conditional, heart-specific transgenic mice with both gain- and loss-of-function for IP(3) receptor signaling to examine its hypertrophic growth effects following pathological and physiological stimulation. METHODS AND RESULTS: Overexpression of the mouse type-2 IP(3) receptor (IP(3)R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca(2+) transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP(3)R2 overexpression failed to augment/synergize cardiac hypertrophy following 2 weeks of pressure-overload stimulation, such levels did enhance hypertrophy following 2 weeks of isoproterenol infusion, in response to Galphaq overexpression, and/or in response to exercise stimulation. To inhibit IP(3) signaling in vivo, we generated transgenic mice expressing an IP(3) chelating protein (IP(3)-sponge). IP(3)-sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP(3)R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-Abeta-null background. CONCLUSION: These results indicate that IP(3)-mediated Ca(2+) release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.

Pubmed ID: 20616315


  • Nakayama H
  • Bodi I
  • Maillet M
  • DeSantiago J
  • Domeier TL
  • Mikoshiba K
  • Lorenz JN
  • Blatter LA
  • Bers DM
  • Molkentin JD


Circulation research

Publication Data

September 3, 2010

Associated Grants

  • Agency: NHLBI NIH HHS, Id: F32 HL090211
  • Agency: NHLBI NIH HHS, Id: R01 HL062231
  • Agency: NHLBI NIH HHS, Id: R01 HL062927
  • Agency: NHLBI NIH HHS, Id: R01 HL062927-12
  • Agency: NHLBI NIH HHS, Id: R37 HL030077
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Age Factors
  • Angiotensin II
  • Animals
  • Arrhythmias, Cardiac
  • Calcineurin
  • Calcium Signaling
  • Cardiomegaly
  • Disease Models, Animal
  • Endothelin-1
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Inositol 1,4,5-Trisphosphate
  • Inositol 1,4,5-Trisphosphate Receptors
  • Isoproterenol
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myocytes, Cardiac
  • Phenotype
  • Physical Exertion