Inositol 1,4,5-trisphosphate receptor (type 1) phosphorylation and modulation by Cdc2 (original) (raw)
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Biochemical and Biophysical Research Communications, 2006
Calcium (Ca 2þ) release from the endoplasmic reticulum (ER) controls numerous cellular functions including proliferation, and is regulated in part by inositol 1,4,5-trisphosphate receptors (IP3Rs). IP3Rs are ubiquitously expressed intracellular Ca 2þ-release channels found in many cell types. Although IP3R-mediated Ca 2þ release has been implicated in cellular proliferation, the biochemical pathways that modulate intracellular Ca 2þ release during cell cycle progression are not known. Sequence analysis of IP3R1 reveals the presence of two putative phosphorylation sites for cyclin-dependent kinases (cdks). In the present study, we show that cdc2/CyB, a critical regulator of eukaryotic cell cycle progression, phosphorylates IP3R1 in vitro and in vivo at both Ser 421 and Thr 799 and that this phosphorylation increases IP3 binding. Taken together, these results indicate that IP3R1 may be a specific target for cdc2/CyB during cell cycle progression.
Distinct Roles of Inositol 1,4,5-Trisphosphate Receptor Types 1 and 3 in Ca2+ Signaling
Journal of Biological Chemistry, 2004
Activation of the phospholipase C pathway by hormones, growth factors, and neurotransmitters results in generation of a second messenger inositol 1,4,5-trisphosphate (IP 3 ), 1 which diffuses to the cytoplasm and binds to an IP 3 receptor (IP 3 R), a Ca 2ϩ release channel on the endoplasmic reticulum (ER) (1). IP 3 R plays key roles in generation of spatially and temporally complex signaling patterns of cytosolic [Ca 2ϩ ] i , such as Ca 2ϩ oscillations. Since not only the amplitude but also the frequency of Ca 2ϩ oscillation is critical for activation of various downstream effectors (2-6), how IP 3 R contributes to these parameters is a key question in the vast area of cell biology.
Regulation of Inositol 1,4,5-Trisphosphate 3-Kinases by Calcium and Localization in Cells
Journal of Biological Chemistry, 2007
Inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ) 3-kinases (IP 3 Ks) are a group of calmodulin-regulated inositol polyphosphate kinases (IPKs) that convert the second messenger Ins(1,4,5)P 3 into inositol 1,3,4,5-tetrakisphosphate. However, what they contribute to the complexities of Ca 2؉ signaling, and how, is still not fully understood. In this study, we have used a simple Ca 2؉ imaging assay to compare the abilities of various Ins (1,4,5)P 3metabolizing enzymes to regulate a maximal histamine-stimulated Ca 2؉ signal in HeLa cells. Using transient transfection, we overexpressed green fluorescent protein-tagged versions of all three mammalian IP 3 K isoforms, including mutants with disrupted cellular localization or calmodulin regulation, and then imaged the Ca 2؉ release stimulated by 100 M histamine. Both localization to the F-actin cytoskeleton and calmodulin regulation enhance the efficiency of mammalian IP 3 Ks to dampen the Ins (1,4,5)P 3 -mediated Ca 2؉ signals. We also compared the effects of the these IP 3 Ks with other enzymes that metabolize Ins(1,4,5)P 3 , including the Type I Ins(1,4,5)P 3 5-phosphatase, in both membrane-targeted and soluble forms, the human inositol polyphosphate multikinase, and the two isoforms of IP 3 K found in Drosophila. All reduce the Ca 2؉ signal but to varying degrees. We demonstrate that the activity of only one of two IP 3 K isoforms from Drosophila is positively regulated by calmodulin and that neither isoform associates with the cytoskeleton. Together the data suggest that IP 3 Ks evolved to regulate kinetic and spatial aspects of Ins (1,4,5)P 3 signals in increasingly complex ways in vertebrates, consistent with their probable roles in the regulation of higher brain and immune function.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2009
The inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) is a universal intracellular Ca 2+ -release channel. It is activated after cell stimulation and plays a crucial role in the initiation and propagation of the complex spatio-temporal Ca 2+ signals that control cellular processes as different as fertilization, cell division, cell migration, differentiation, metabolism, muscle contraction, secretion, neuronal processing, and ultimately cell death. To achieve these various functions, often in a single cell, exquisite control of the Ca 2+ release is needed. This review aims to highlight how protein kinases and protein phosphatases can interact with the IP 3 R or with associated proteins and so provide a large potential for fine tuning the Ca 2+ -release activity and for creating efficient Ca 2+ signals in subcellular microdomains.
Biochemical and Biophysical Research Communications, 1991
IP3 activates intracellular calcium release by binding to an intracellular ligand gated calcium permeable channel which has been shown to be regulated by protein kinase A phosphorylation. Two consensus sequences for protein kinase A phosphorylation are predicted by the recently isolated cDNA of the mouse and rat. In the present study we have isolated and sequenced the two peptides in the rat IP3 receptor which are phosphorylated by protein kinase A and demonstrate protein kinase A phosphorylation on S-1755 and S-1589.
Inositol 1,4,5-trisphosphate receptor subtype-specific regulation of calcium oscillations
2011
Oscillatory fluctuations in the cytosolic concentration of free calcium ions (Ca 2?) are considered a ubiquitous mechanism for controlling multiple cellular processes. Inositol 1,4,5-trisphosphate (IP 3) receptors (IP 3 R) are intracellular Ca 2? release channels that mediate Ca 2? release from endoplasmic reticulum (ER) Ca 2? stores. The three IP 3 R subtypes described so far exhibit differential structural, biophysical, and biochemical properties. Subtype specific regulation of IP 3 R by the endogenous modulators IP 3 , Ca 2? , protein kinases and associated proteins have been thoroughly examined. In this article we will review the contribution of each IP 3 R subtype in shaping cytosolic Ca 2? oscillations.
Proceedings of the National Academy of Sciences, 2005
Virtually all functions of a cell are influenced by cytoplasmic [Ca 2؉ ] increases. Inositol 1,4,5-trisphosphate receptor (IP3R) channels, located in the endoplasmic reticulum (ER), release Ca 2؉ in response to binding of the second messenger, IP3. IP3Rs thus are part of the information chain interpreting external signals and transforming them into cytoplasmic Ca 2؉ transients. IP3Rs function as tetramers, each unit comprising an N-terminal ligand-binding domain (LBD) and a C-terminal channel domain linked by a long regulatory region. It is not yet understood how the binding of IP3 to the LBD regulates the gating properties of the channel. Here, we use the expression of IP3 binding protein domains tethered to the surface of the endoplasmic reticulum (ER) to show that the all-helical domain of the IP3R LBD is capable of depleting the ER Ca 2؉ pools by opening the endogenous IP3Rs, even without IP3 binding. This effect requires the domain to be within 50 Å of the ER membrane and is impaired by the presence of the N-terminal inhibitory segment on the LBD. These findings raise the possibility that the helical domain of the LBD functions as an effector module possibly interacting with the channel domain, thereby being part of the gating mechanisms by which the IP3-induced conformational change within the LBD regulates Ca 2؉ release.