Post-transcriptional control of type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2) by microRNA during cardiac hypertrophy

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

The beating of the heart as it pumps blood around the body is induced by an increase in the amount of calcium in its muscle cells. This increase in calcium is brought about through the entry of calcium into the cell from the extracellular space, which then causes release of calcium from calcium stores in the cell. The movement of calcium within the cell occurs through channel proteins, which span the outer membrane of the cell and the membranes that bound the intracellular calcium stores. Following the induction of contraction of the cardiac muscle cells, relaxation is then brought about by the action of energy consuming pumps, which transport calcium back into the stores and out of the cell. This project focuses upon the regulation of expression of an intracellular calcium channel called the IP3R in the muscle cells of the heart that plays a relatively minor role in regulation of contraction in the young healthy heart. With the onset of disease or ageing, the abundance of this channel is increased causing extra calcium increases in the cell, which may induce arrhythmias or inappropriate cardiac growth. Both of these effects can lead to heart failure and death. The mechanism by which we consider that the expression of the IP3R is regulated is through a small fragment of RNA called a microRNA. Our preliminary evidence suggests that the amount of this microRNA is decreased by calcium release from the IP3R. Due to the decrease in the microRNA, which normally suppresses IP3R expression, IP3R expression is allowed to increase. As such, it appears that the IP3R controls its own abundance through calcium and microRNA abundance.

Publications

10 25 50
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Bootman MD (2011) Atrial cardiomyocyte calcium signalling. in Biochimica et biophysica acta

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Fearnley CJ (2011) Calcium signaling in cardiac myocytes. in Cold Spring Harbor perspectives in biology

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Thul R (2012) Subcellular calcium dynamics in a whole-cell model of an atrial myocyte. in Proceedings of the National Academy of Sciences of the United States of America

 
Description calcium increases inside the muscle cells of the heart is important for heart function. One way by which calcium is increased in heart cells is by release from intracellular reservoirs via IP3 receptor channels. We have shown that this way of generating a calcium signal can cause arrhyhtmia and cardiac growth. in this project, we found that calcium release via this channel also regulated the amount of a small microRNA in cells called miR-133. Others have shown that this microRNA ordinarily inhibits cardiac growth. We found that this microRNA also put a break on the amount of IP3 receptor channels in a cells. We also found that calcium from the IP3R reduced the amount of the microRNA. Thus, by reducing miR-133 expression, IP3 receptors could control their own expression and as a consequence how they affected cardiac function.
Exploitation Route by targeting the interaction between the microRNA and IP3 receptors, others may find ways to control cardiac arrhythmia and cardiac growth - possibly killing two birds with one stone.
Sectors Pharmaceuticals and Medical Biotechnology

URL http://jcb.rupress.org/content/199/5/783
 
Description Odysseus FWO
Amount € 837,974 (EUR)
Funding ID 90663 
Organisation Research Foundation - Flanders (FWO) 
Sector Charity/Non Profit
Country Belgium
Start 10/2014 
End 09/2019
 
Description Project Grant
Amount € 472,485 (EUR)
Funding ID G08861N 
Organisation Research Foundation - Flanders (FWO) 
Sector Charity/Non Profit
Country Belgium
Start 01/2016 
End 12/2019
 
Description Catalucci 
Organisation Institute of Genetic and Biomedical Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of effect of micro RNA on heart growth
Collaborator Contribution Provision of hearts from mice injected with miRNA inhibitor.
Impact 23166348
Start Year 2011
 
Description Conway 
Organisation University of Oxford
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution USe and testing of cell permeant IP3 analogues
Collaborator Contribution Provision of Cell permeant IP3 analogues
Impact 23166348 20106523 19934645 19549843 19250908 18407350 18250332 17692540 17585817 17574672 16882691 16814379 15561771 15263017 14685260 12767897
 
Description MIkoshiba 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution Analysis of tissue from itpr2 KO animals Use of IP3R2 monoclonal Antibody
Collaborator Contribution Provision of IP3R2 monoclonal antibody. Provision of heart tissue from IP3R2 KO animals
Impact Publication in JCB: 23166348 Publication in Mol Cell: 19250908
 
Description Molkentin 
Organisation Cincinnati Children's Hospital Medical Center
Department Department of Pediatrics
Country United States 
Sector Academic/University 
PI Contribution Analysed the mice
Collaborator Contribution The collaborator provided hearts from control and aortically constricted mice transgenic for the IP3R Ligand binding domain and for type 2 IP3 receptors.
Impact Publication in Journal of Cell Biology in 2012 23166348
Start Year 2011
 
Description Norway Rats 
Organisation University of Oslo
Department Institute for Experimental Medical Research
Country Norway 
Sector Academic/University 
PI Contribution Analysis of Cardiac Myocyte proteome, transcriptome and epigenome.
Collaborator Contribution Provision and phenotyping of hearts hypertrophic due to exercise, aortic banding or ageing.
Impact Publication in JCB in 2012 27893464 23166348
Start Year 2009
 
Description Ritter 
Organisation University of Wurzburg
Country Germany 
Sector Academic/University 
PI Contribution Analysis of Cardiac tissue from aortically constricted mice. Analysis of effect of cell permeant peptide that prevents calcineurin nuclear import upon NFAT accumulation in the nucleus.
Collaborator Contribution Provision of tissue from surgically prepared mice. Provision of cell permeant peptide. Provision of GFP-tagged calcineurin expression vectors.
Impact Publication in Mol Cell: 19250908 Publication in PNAS: 19549843
Start Year 2007
 
Description UT SW 
Organisation University of Texas Southwestern Medical Center
Country United States 
Sector Academic/University 
PI Contribution Analysis of Tissue from miR-133 DKO animals
Collaborator Contribution Provision of tissue and mRNA from miR-133 double knockout animals
Impact Publication in JCB in 2012: 23166348
Start Year 2010
 
Description 2. September 2013. Cambridge-Yale Cardiovascular Meeting, Yale, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Interacted with clinicians and scientists from Yale and Cambridge
50 attendees at meeting.


Useful interactions made that may progress to formal collaborations.
Year(s) Of Engagement Activity 2013
 
Description 3. June 2013. Calcium Signalling Gordon Research Conference. Il Ciocco. Italy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 200 Participants.

Valuable interactions subsequent
Year(s) Of Engagement Activity 2013
 
Description Invited Speaker - Biochemical Society meeting 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk provoked interest and discussions.


Possible collaborations initiated
Year(s) Of Engagement Activity 2014