Nuclear translocation of calmodulin in pathological cardiac hypertrophy originates from ryanodine receptor bound calmodulin.

Abstract

In cardiac myocytes Calmodulin (CaM) bound to the ryanodine receptor (RyR2) constitutes a large pool of total myocyte CaM, but the CaM-RyR2 affinity is reduced in pathological conditions. Knock-in mice expressing RyR2 unable to bind CaM also developed hypertrophy and early death. However, it is unknown whether CaM released from this RyR2-bound pool participates in pathological cardiac hypertrophy. We found that angiotensin II (AngII) or phenylephrine (PE) both cause CaM to dissociate from the RyR2 and translocate to the nucleus. To test whether this nuclear CaM accumulation depends on CaM released from RyR2, we enhanced CaM-RyR2 binding affinity (with dantrolene), or caused CaM dissociation from RyR2 (using suramin). Dantrolene dramatically reduced AngII- and PE-induced nuclear CaM accumulation. Conversely, suramin enhanced nuclear CaM accumulation. This is consistent with nuclear CaM accumulation coming largely from the CaM-RyR2 pool. CaM lacks a nuclear localization signal (NLS), but G-protein coupled receptor kinase 5 (GRK5) binds CaM, has a NLS and translocates like CaM in response to AngII or PE. Suramin also promoted GRK5 nuclear import, and caused nuclear export of histone deacetylase 5 (HDAC5). Dantrolene prevented these effects. After 2-8 weeks of pressure overload (TAC) CaM binding to RyR2 was reduced, nuclear CaM and GRK5 were both elevated and there was enhanced nuclear export of HDAC5. Stress (acute AngII or TAC) causes CaM dissociation from RyR2 and translocation to the nucleus with GRK5 with parallel HDAC5 nuclear export. Thus CaM dissociation from RyR2 may be an important step in driving pathological hypertrophic gene transcription.

• Authors: Tetsuro Oda, Takeshi Yamamoto, Takayoshi Kato, Hitoshi Uchinoumi, Go Fukui, Yoriomi Hamada, Takuma Nanno, Hironori Ishiguchi, Yoshihide Nakamura, Yoko Okamoto, Michiaki Kono, Shinichi Okuda, Shigeki Kobayashi, Donald M Bers, Masafumi Yano
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 125 Pg. 87-97 (12 2018) ISSN: 1095-8584 [Electronic] England
• PMID: 30359562 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Calmodulin
• Nuclear Localization Signals
• Receptors, G-Protein-Coupled
• Ryanodine Receptor Calcium Release Channel
• Angiotensin II
• Phenylephrine
• Suramin
• Hdac5 protein, mouse
• Histone Deacetylases
• Dantrolene

Topics

• Angiotensin II (pharmacology)
• Animals
• Biological Transport (drug effects)
• Calmodulin (metabolism)
• Cardiomegaly (metabolism)
• Cell Nucleus (metabolism)
• Cells, Cultured
• Dantrolene (pharmacology)
• Histone Deacetylases (metabolism)
• Mice
• Nuclear Localization Signals (metabolism)
• Phenylephrine (pharmacology)
• Receptors, G-Protein-Coupled (metabolism)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Suramin (pharmacology)