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Bcl-2 is an important regulator of inositol 1,4,5-trisphosphate receptor (IP3R) activity and, thus of Ca2+ release from internal stores and associated processes, including cellular proliferation and death. The presence of multiple regulatory domains in both proteins suggests a complex interaction. Earlier reports have shown the involvement of both the BH4 and the transmembrane domains of Bcl-2 in regulating IP3R activity, while the Bcl-2 hydrophobic cleft was associated primarily with its anti-apoptotic, IP3R-independent, action at the mitochondria. Here, we show that occlusion of Bcl-2’s hydrophobic cleft by the drug ABT-199 finely modulates IP3R gating in the low open probability regime, characteristic of the basal IP3R activity in non-excited cells. Complementary MD simulations allowed us to propose a model of this modulation, involving an allosteric interaction with the BH4 domain on the opposite side of Bcl-2.

Store-operated calcium entry (SOCE) plays important roles in a multitude of cellular processes, from muscle contraction to cellular proliferation and migration. Dysregulation of SOCE is responsible for the advancement of multiple diseases, ranging from immune diseases, myopathies, to terminal ones like cancer. Naturally, SOCE has been a focus of many studies and review papers which, however, primarily concentrated on the principal players localized to the plasma membrane and responsible for Ca

Store-operated calcium entry (SOCE) plays important roles in a multitude of cellular processes, from muscle contraction to cellular proliferation and migration. Dysregulation of SOCE is responsible for the advancement of multiple diseases, ranging from immune diseases, myopathies, to terminal ones like cancer. Naturally, SOCE has been a focus of many studies and review papers which, however, primarily concentrated on the principal players localized to the plasma membrane and responsible for Ca2+ entry into the cell. Much less has been said about other players participating in the entire SOCE event. This review aims to address this shortcoming by discussing the accumulated scientific knowledge focused on the inositol trisphosphate receptors (IP3Rs), principal player responsible for emptying intracellular Ca2+ stores in a majority of cells, and their involvement in regulation of cell migration and invasion in cancer.