Sitsapesan Group | Intracellular Ion Channels and Ca²⁺ Release

The group

Our research focuses on the structure and function of ion channels present on intracellular Ca²⁺ stores. This provides insight into how changes in cellular Ca²⁺ homeostasis can lead to severe disease such as heart failure, high blood pressure or osteogenesis imperfecta.

For example, we are investigating how the opening of the main intracellular Ca²⁺-release channel present in heart cells, the ryanodine receptor, is modulated by closely associated proteins, by drugs and by mutations that cause sudden cardiac death.    

We are collaborating with colleagues in Japan (Hiroshi Takeshima group) to study the function of novel ion channels such as Mitsugumin 23 (MG23), thought to play a role in cell death and cancer, and the trimeric intracellular ion channels (TRIC-A and TRIC-B) which are essential for normal intracellular Ca²⁺ release in many different cell types. In addition, we collaborate with Antony Galione (Pharmacology) to investigate the properties of Ca²⁺ release channels on lysosomes.  We expect our investigations to expose many novel sites on intracellular Ca²⁺-stores as targets for therapeutic intervention.

Our research

We are studying the biophysical properties and putative physiological roles of ion-channels present on intracellular Ca²⁺-stores. Although we are particularly interested in their relevance in the heart, these ion-channels are also crucial to the normal physiology of many other organs, including the lungs, kidney, brain, vascular smooth muscle and skeletal muscle. A major aspect of our work is the function of the ryanodine receptor Ca²⁺-release channel (RyR) and how the regulation of this channel is altered in heart failure and in inherited arrhythmic conditions that can lead to sudden cardiac death.

We are also investigating the single-channel behaviour of the putative Ca²⁺-release channels present on acidic lysosomal stores; the two-pore channels (TPC1, TPC2). Our recent publications demonstrated that although both channels are permeable to Ca²⁺, they exhibit marked differences in gating behaviour and in their permeability properties.

There are other ion-channels that support the process of Ca²⁺-release but whose exact physiological roles have not been fully identified. These include the two sub-types of trimeric intracellular cation channel (TRIC-A and TRIC-B) that are present in the SR and nuclear membranes of most cells. Abnormalities in TRIC-A and/or TRIC-B are associated with a range of diseases including embryonic heart failure, respiratory failure, hypertension and the bone disorder, osteogenesis imperfecta. We are examining the relationships between structure and function of the TRIC channels in order to better understand their physiological roles in the heart and other organs. We are also investigating the function of the non-selective cation channel Mitsugumin 23 (MG23) which is present in the SR and nuclear membranes of all cells. This ion channel is proposed to be activated under conditions of cell stress and is a target for the treatment of cancer.