Intracellular calcium signalling in health and disease
Intracellular Ca2+ is a key signalling messenger in virtually all eukaryotic cells. We are interested in how these signals are generated, how the subsequent Ca2+ rise controls the function of mammalian cells and how aberrant Ca2+ signals contribute to human diseases including allergy, asthma and hypertension.
Cytoplasmic Ca2+ is a universal intracellular signalling messenger that activates a wide range of fundamental cellular responses including neurotransmitter release, muscle contraction, enzyme activation and cellgrowth and differentiation. A rapid and effective way for cells toincrease intracellular Ca2+ is through the opening of calcium channels in the plasma membrane.
Research in our laboratory is focused on molecular mechanisms that control intracellular calcium signaling through plasma membrane store-operated Ca2+ channels and how these calcium signals are altered in human disease. Store-operated Ca2+ channels are gated in a unique way; they open following the depletion of Ca2+ from the lumen of the endoplasmicreticulum, brought about after stimulation of cell surface receptors that increase the levels of the second messenger IP3. One important and widespread member of the store-operated Ca2+ channel family is the Ca2+ release-activated Ca2+ channel or CRAC channel.
Ca2+ entry through CRAC channels contributes to myriad responses including secretion, metabolism, gene expression, and cell differentiation. CRAC channels are extremely important in the immune system, where they help regulate T lymphocyte and mast cell function. A single point mutation in the gene encoding the pore-forming subunit of the CRAC channel leads to adevastating immunodeficiency in humans as well as muscle weakness, and abnormalities in the skin, hair, and teeth.
We have three main research themes. One major effort is to understand how loss of Ca2+ from the endoplasmic reticulum leads to CRAC channel opening. Recent work has established that upon store depletion, the ER Ca2+ sensor protein STIM1 forms multimeric complexes, which then migrate across the ER to specialised regions just below the plasma membrane. Here, STIM1 proteins bind to and open Orai1proteins, which are central components of the CRAC channel. How STIM1 moves across the endoplasmic reticulum and how it interacts with Orai1 are questions we are studying.
A second major effort is to understand how Ca2+ signals near CRAC channels activate downstream responses such as mitochondrial metabolism and gene expression. We have found that spatially restricted Ca2+ signals, called Ca2+ microdomains, are particularly effective in activating these pathways especially in response to physiological levels of simulation. How are the Ca2+ signals detected and how are they relayed to their targets?
A third project concerns the role of CRAC channels in human disease. We are investigating how the channels are altered in respiratory disorders including those that affect both upper and lower airways (nasal polyposis/allergic rhinitis and asthma, respectively).