Calcium signaling has been identified as an important phenomenon in a plethora of cellular processes. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ER-residing intracellular calcium (Ca2+) release channels responsible for cell bioenergetics by transferring calcium from the ER to the mitochondria. The recent availability of full-length IP3R channel structure has enabled the researchers to design the IP3 competitive ligands and reveal the channel gating mechanism by elucidating the conformational changes induced by ligands. However, limited knowledge is available for IP3R antagonists and the exact mechanism of action of these antagonists within a tumorigenic environment of a cell. Here in this review a summarized information about the role of IP3R in cell proliferation and apoptosis has been discussed. Moreover, structure and gating mechanism of IP3R in the presence of antagonists have been provided in this review. Additionally, compelling information about ligand-based studies (both agonists and antagonists) has been discussed. The shortcomings of these studies and the challenges toward the design of potent IP3R modulators have also been provided in this review. However, the conformational changes induced by antagonists for channel gating mechanism still display some major drawbacks that need to be addressed. However, the design, synthesis and availability of isoform-specific antagonists is a rather challenging one due to intra-structural similarity within the binding domain of each isoform. HighlightsThe intricate complexity of IP3R's in cellular processes declares them an important target whereby, the recently solved structure depicts the receptor's potential involvement in a complex network of processes spanning from cell proliferation to cell death.Pharmacological inhibition of IP3R attenuates the proliferation or invasiveness of cancers, thus inducing necrotic cell death.Despite significant advancements, there is a tremendous need to design new potential hits to target IP3R, based upon 3D structural features and pharmacophoric patterns.Communicated by Ramaswamy H. Sarma.
Keywords: 3D structures; Ca2+ signaling; IP3R; IP3R agonists; IP3R antagonists; biological regulatory network; cancer.