Ca2+ is a ubiquitous intracellular signaling messenger regulating a wide range of functions including enzyme activation, gene expression, chemotaxis, and neurotransmitter release. Cellular Ca2+ signals arise from the opening of Ca2+ permeable ion channels, a diverse family of membrane proteins. We study Ca2+ signals arising from store-operated Ca2+ channels (SOCs), a family of plasma membrane ion channels that are activated by a decrease in the calcium content of the endoplasmic reticulum (ER), an intracellular organelle that serves as a reservoir for storing calcium. Human patients with mutations in SOCs suffer from a devastating immunodeficiency, muscle weakness, and abnormalities in the skin, hair, and teeth, underscoring the vital importance of SOCs for human health. We study the molecular and cellular mechanisms by which SOCs are activated and the mechanisms by which they regulate gene expression, immune cell function, and neuronal and astrocyte functions. Current projects are focussed on three areas: (1) mechanisms of CRAC channel gating, including the conformation dynamics of channel opening and closing. (2) The role of CRAC channels in the brain including control of synaptic plasticity, astrocyte and microglial-mediated neuroinflammation, and implications for neuropathic pain and behavioral depression, and, (3) The contributions of Orai channels for airway inflammation in the lung especially in the context of asthma.