Dr. Lewis's research in the laboratory is focused on the molecular mechanisms of calcium signaling through store-operated Ca²⁺ channels (SOCs). This class of ion channels is regulated in a unique way, by the depletion of Ca²⁺ from the lumen of the endoplasmic reticulum (ER) which normally occurs following stimulation of cell surface receptors that generate IP3. They are expressed in practically all cells, where they contribute to diverse functions including secretion, gene expression, and cell differentiation. A SOC called the Ca²⁺ release-activated Ca²⁺ channel, or CRAC channel, is particularly important in T cells, where it generates sustained Ca²⁺ signals that are essential for triggering T cells to proliferate and carry out immune functions. Loss of function of the CRAC channel by a single mutation in its structural gene leads to a devastating severe combined immunodeficiency (SCID) syndrome in humans.

A major effort in the lab is to understand how the depletion of Ca²⁺ from the ER triggers the opening of CRAC channels in the plasma membrane.