Calcium oscillations form the signalling basis for a plethora of biologically relevant processes ranging from muscular contraction to cellular division and apoptosis.
Regulation of these oscillations is primarily controlled by the sarco / endoplasmic reticulum Ca2+ ATPase (SERCA) pump and the inositol trisphosphate receptor (IP3R), with the frequency of oscillations encoding the cellular information.
In particular, dysregulation in astrocytes (support cells in the brain) have been linked to various diseases such as epilepsy and cancer and as such a great deal of research is interested in the underlying mechanisms to aid the development of novel therapies.
Figure 1 - Protein crystal structures for the SERCA (top) and IP3R enzymes (bottom)
There are two key mechanisms that are thought to underpin the concentration of Ca2+ in the cytosol.
First is the calcium induced calcium released flux of ions into the sarco/endoplasmic reticulum via the SERCA pump. Second is calcium dependent production of IP3 which releases Ca2+ into the cytosol through the IP3R.
These processes are then modulated via passive leak and voltage gated calcium channels situated in the plasma membrane.
Figure 2 - Schematic of Ca2+ regulatory mechanisms
This project investigated the effects of conformational change in these structures, usually caused either by genetic predisposition or mutation, on the frequency of Ca2+ oscillations through mathematical simulation. The conformational changes were achieved through manipulation of key parameters dictating Ca2+ ion flow through both of the enzymes.
The simulations indicated that conformational changes associated with increasing the cytosolic Ca2+ concentration (such as looser structures) results in increased frequency of oscillation. This can be linked to the cellular over excitation characterised by diseases such as epilepsy.
Figure 3 - Changes in calcium oscillation with increasing mIP3R
School of Mathematical Sciences, University of NottinghamUniversity Park NG7 2RD
Tel: +44 (0) 115 823 2376 Fax: +44 (0) 115 951 3555 Email: naturalsciences@nottingham.ac.uk