Intracellular calcium store within the endoplasmic reticulum (ER) plays a critical role in controlling many cellular events like secretion, ER-stress, protein folding, apoptosis etc. Perturbation of ER calcium homeostasis may lead to several diseases like neurodegenerative diseases, diabetes and cancer. ER calcium level is maintained by the interplay of several transporters, channels and calcium binding proteins. ER-resident protein SERCA (sarco-endoplasmic-reticulum calcium-ATPase) actively pumps calcium into the ER, whereas IP3 receptors remove calcium from ER upon its activation by IP3. calcium from ER goes out passively by ‘leak channel’. The identity and properties of ‘leak channel’ are not very clear though several proteins like presenilin and Bcl-2 have been implicated in the process of calcium leak from ER. Recently we showed that LRRC8B (Leucine-rich repeat-containing 8) protein is a major player of cellular calcium signaling and a legitimate leak channel. We are studying the involvement of LRRC8B in calcium homeostasis in detail.   

Pannexins are the channel forming proteins, ubiquitously expressed in many cell types including glial cells and neuron. Pannexins have been implicated in many physiological as well as pathophysiological processes. Hyperactivation of pannexins have been linked to neuroinflammation and neurodegeneration. In glial cells, pannexin-1 works as a major gliotransmitter release channel during inflammation. ATP, released through panneanxin-1 channel triggers varieties of signaling cascades both in paracrine and autocrine fashion. ATP acts on P2X and P2Y receptors leading to increase of intracellular calcium which is followed by the activation of different signaling pathways. It has been shown that pannexin-1 couples with P2X7 receptor and they work in concert regulating different cellular events. During neuroinflammation, ATP released through pannexin-1 channel activates P2X7 receptor causing excessive rise of intracellular calcium and thereby promotes cell death. We are studying the role of Pannexin-1/P2X7 in Parkinson’s disease and ischemia.  

In India, more than a million people suffer strokes each year. During ischemic stroke, insufficient oxygen supply to the brain tissue is followed by a drop in extracellular pH that in turn activates calcium-permeable ‘Acid-Sensing Ion Channels’ (ASICs). The excessive rise in intracellular calcium is believed to be one of the causes of neuronal death. Although the crystal structure of ASIC has been published recently, the mechanism of ASIC-opening/closing (gating) is not clear. We are studying the conformational changes that occur during channel gating from the closed to open/desensitized states. We are also trying to find out small molecules for treating stroke by blocking ASICs.