Parekh Group

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).