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Title: Inositol 1,4,5-trisphosphate-dependent calcium signalling in the nuclear microdomain is a requisite signal for cardiac hypertrophy
Author: Fearnley, C. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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The pro-hypertrophic action of the peptide hormone endothelin-1 (ET-1) is dependent on IP3-induced Ca2+ release (IICR). However, it remains to be fully understood how this pro-hypertrophic Ca2+ signal is detected above constantly oscillating Ca2+ transients controlling ECC. Ventricular cardiac myocytes possess a perinuclear population of IP3Rs. In this thesis, I have identified that Ca2+ release via these perinuclear IP3Rs mediates a nuclear-localised Ca2+ signal that is required for the induction of cardiac hypertrophy by ET-1. Furthermore, I have revealed that the calcineurin-nuclear factor of activated T cells (Cn-FNAT) pathway is engaged by IICR to induce hypertrophy. By manipulating Ca2+ in the cytosol and nucleus, I established that activation of the Cn-NFAT pathway and transcription of hypertrophy-associated genes is dependent on Ca2+ signalling in both regions. These findings suggest a model in which perinuclear IICR activates cytosolic Cn, which then dephosphorylates and activates NFAT, causing NFAT translocation to the nucleus. IICR in the nuclear compartment maintains the transcriptional competence of NFAT by continuing its activation by Cn, with which it interacts in this location. This model provides a robust mechanism for the controlled regulation of Cn-NFAT, and activation of this pathway specifically in response to pro-hypertrophic stimuli.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available