IP3 receptors: An “elementary” journey from structure to signals

Agonist-Induced Ca2+ Signaling in HEK-293-Derived Cells Expressing a Single IP3 Receptor Isoform

“…Extracellular cues regulate diverse cellular functions by involving a variety of surface receptors and intracellular signaling pathways. The mobilization of intracellular Ca 2+ is central to transduction of many first messengers that act through G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) coupled to the phosphoinositide cascade [1][2][3]. GPCRs stimulate the phosphoinositide cascade by involving the β1-4 isoforms of phospholipase C (PLC) in a αGqand/or βγGi-dependent manner, while RTKs employ PLCγ [2][3][4][5][6].…”

“…The mobilization of intracellular Ca 2+ is central to transduction of many first messengers that act through G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) coupled to the phosphoinositide cascade [1][2][3]. GPCRs stimulate the phosphoinositide cascade by involving the β1-4 isoforms of phospholipase C (PLC) in a αGqand/or βγGi-dependent manner, while RTKs employ PLCγ [2][3][4][5][6]. Once stimulated, PLC produces two second messengers, IP 3 and diacylglycerol, by hydrolyzing the precursor lipid phosphatidylinositol 4,5-bisphosphate.…”

“…Once stimulated, PLC produces two second messengers, IP 3 and diacylglycerol, by hydrolyzing the precursor lipid phosphatidylinositol 4,5-bisphosphate. The primary mode of action of IP 3 is to release Ca 2+ from Ca 2+ store through IP 3 receptors (IP 3 Rs) [1,3]. Three genes encode IP 3 R subunits IP 3 R1, IP 3 R2, and IP 3 R3, which form primarily homotetrameric IP 3 -gated Ca 2+ channels in the endoplasmic reticulum (ER).…”

“…Three genes encode IP 3 R subunits IP 3 R1, IP 3 R2, and IP 3 R3, which form primarily homotetrameric IP 3 -gated Ca 2+ channels in the endoplasmic reticulum (ER). Moreover, evidence exists that different IP 3 R subunits also can form heterotetrameric complexes with specific functional and regulatory properties [3,[7][8][9][10]. This and alternative splicing of the IP 3 R genes increase the functional heterogeneity of IP 3 -gated channels, posing an additional complexity to studying physiological functions and regulations of IP 3 Rs in cells [11,12].…”

“…Since agonist-induced IP 3 /Ca 2+ signaling is pivotal to the physiology of apparently all cell types, IP 3 Rs were subjected to intensive studies at molecular, biophysical, and functional levels [1,3,9,10,18]. Reportedly, all IP 3 R isoforms are regulated by cytosolic Ca 2+ in a bimodal manner, suggesting that IP 3 Rs hold two allosteric Ca 2+ -binding sites, both activatory and inhibitory [1,3,19,20]. Although the activatory site has been identified, the structure and location of the inhibitory site is still debatable [3].…”