Ca²⁺ is a universal second messenger that regulates wide variety of functions in virtually all cell types. These cellular functions include muscle contraction, neuronal transmission, fluid secretion, cell migration, cell growth, gene transcription and cell death. Cytosolic Ca²⁺ increases in response to stimulation by receptor agonists and this rise in cytosolic Ca²⁺ can originate from either internal stores, mainly the endoplasmic reticulum (ER) or from the extracellular space through Ca²⁺ entry mediated by plasma membrane channels. Mitochondria can uptake cytosolic Ca²⁺ originating from both Ca²⁺ release and entry and this mitochondrial Ca²⁺ uptake couples agonist activation to ATP production. Mitochondrial Ca²⁺ uptake and extrusion are mediated by the mitochondrial Ca²⁺ uniporter (MCU) and the mitochondrial Na^+/Ca²⁺ exchanger (NCLX), respectively. One major route of ER Ca²⁺ release involves the phosphoinositide (PI) pathway. Ligation of plasma membrane receptors that couple to specific phospholipase C (PLC) isoforms results in the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP₂) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃). DAG is most known for activating protein kinase C (PKC) while IP₃ causes Ca²⁺ release from ER stores through the IP₃ receptor (IP₃R).

Activation of the PI pathway also leads to Ca²⁺ entry across the plasma membrane through diverse mechanisms. It is increasingly appreciated that second messengers generated downstream of the PI pathway (e.g. DAG, Ca²⁺, arachidonic acid and its metabolites, PIP₂ breakdown itself) activate Ca²⁺ entry channels located in the plasma membrane, including members of the broader TRP channel family. For example, DAG has been recognized for activating (in a PKC-independent manner) members of the canonical TRP channel family, TRPC3/6/7. In addition, Ca²⁺ release from the ER through the action of IP₃ on the IP₃R causes depletion of these ER stores. The depletion of Ca²⁺ concentration within ER lumen activates the single transmembrane ER-resident Ca²⁺-sensor protein STIM1 through loss of Ca²⁺ binding to a low affinity Ca²⁺-binding EF hand in STIM1 N-terminus. STIM1 then undergoes conformational change prompting its oligomerization in ER-plasma membrane junctional areas and STIM1 C-terminus extends to directly trap and activate ORAI1 channels. This process of Ca²⁺ entry is known as store-operated Ca²⁺ entry (SOCE) and the electrical current it mediates is commonly known as Ca²⁺ release-activated Ca²⁺ (CRAC) current. STIM1 has another homolog, STIM2 that is activated by modest levels of store depletion compared to STIM1. ORAI1 has two homologs in mammals, ORAI2 and ORAI3 which remain poorly understood.

Several projects are currently ongoing in the laboratory:

1) Molecular mechanisms of CRAC channel activation, assembly and  regulation, including mechanisms of channel inactivation and regulation by post-translational modifications

2) Role of STIM, ORAI and TRP proteins in endothelial permeability and migration

3) STIM proteins in airway smooth muscle remodeling during asthma

4) Cell-specific functions of ORAI channel isoforms and their contribution to vascular remodeling during chronic hypertension

5) Non canonical signaling functions of STIM and ORAI isoforms in colorectal cancer growth and metastasis

6) Physiological functions of the mitochondrial Ca²⁺ uniporter (MCU) and mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) and their participation in cancer progression, metastasis and chemoresistance.

Research in the laboratory is made possible through grants from the National Heart Lung and Blood Institute, the National Institute on Aging, and the National Institute of Environmental Health Sciences of the National Institutes of Health; the American Heart Association; and funds from the Qatar National Research Fund of the Qatar Foundation.