BHF Intermediate Basic Science Research Fellow
In mammalian muscle cells Ca2+ cycles through the sarcoplasmic reticulum (SR) in a coordinated manner, causing cell contraction and relaxation. Most of the Ca2+ that leads to cell contraction is released from the SR through specialised Ca2+-release channels called ryanodine receptors (RyR). RyRs play a very important role in muscle cell function. In the heart for example, mutations to RyR2, the cardiac isoform of RyRs, can lead to abnormal Ca2+-cycling through the SR and aberrant contractions that can then trigger arrhythmias and sudden cardiac death. Impaired RyR2 function has been linked to cardiac diseases, such as heart failure, catecholaminergic polymorphic ventricular tachycardia (CPVT) and other inherited arrhythmic conditions. Similarly, mutations to RyR1, the skeletal muscle isoform of RyRs, have been associated with diseases such as malignant hyperthermia and central core disease. Importantly, RyRs are also abundantly expressed in the brain participating in Ca2+-signalling pathways in neuronal processes, such as modulation of neurotransmitter release and synaptic plasticity, whereas mutations in RyR2 have been linked to seizures and epilepsy.
Our research focuses in the study of the structure and the function of RyRs under normal and pathological conditions in the cardiac and skeletal muscle, and also in the brain. Our ultimate goal is to provide insight into how intracellular Ca2+-dysregulation can lead to disease. Additionally, we investigate novel compound interactions with RyRs to identify and develop new treatments for RyR-related diseases.
Biophysical characteristics of TRIC-A and TRIC-B channels and their regulation of RYR2.
Hu J. et al, (2022), J Gen Physiol, 154
The V2475F CPVT1 mutation yields distinct RyR2 channel populations that differ in their responses to cytosolic Ca2+ and Mg2.
Wilson AD. et al, (2021), J Physiol, 599, 5179 - 5201
The Malignant Hyperthermia G2435R Mutation Causes Constitutive RYR1 Openings
Humberstone TM. et al, (2021), BIOPHYSICAL JOURNAL, 120, 111A - 111A
Combining tissue engineering and optical imaging approaches to explore interactions along the neuro-cardiac axis: Neuro-cardiac research
Sigalas C. et al, (2020), Royal Society Open Science, 7
Combining tissue engineering and optical imaging approaches to explore interactions along the neuro-cardiac axis.
Sigalas C. et al, (2020), R Soc Open Sci, 7