Inositol 1,4,5-Trisphosphate Receptors as Signal Integrators

Patterson, Randen L.; Boehning, Darren; Snyder, Solomon H.

doi:10.1146/annurev.biochem.73.071403.161303

Cited by 412 publications

(427 citation statements)

References 179 publications

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“…This effect of ouabain is most likely due to the activation of Src. First, prior studies showed that Src family kinases could phosphorylate IP3R1 isoform (Jayaraman et al, 1996;Yokoyama et al, 2002;Cui et al, 2004;Patterson et al, 2004). Second, inhibition of Src abolished ouabain-induced tyrosine phosphorylation of the receptor (Figure 7).…”

Section: Regulation Of Plc-␥1 and Ip3r2 By The Activated Na/katpase Smentioning

confidence: 83%

“…Because the activated PLC-␥1 produces the ligand (IP3) of IP3 receptors, we tested whether the ouabain-activated complex could also recruit IP3 receptors in LLC-PK1 cells. Furthermore, we also tested whether the same ouabain-activated complex stimulates the tyrosine phosphorylation of IP3 receptors because Src family kinases can phosphorylate these receptors, resulting in increased sensitivity to IP3 (Jayaraman et al, 1996;Yokoyama et al, 2002;Cui et al, 2004;Patterson et al, 2004). As depicted in Figure 6A, we identified all three isoforms of IP3 receptors from LLC-PK1 cell lysates with commercially available antibodies.…”

Section: Ouabain-activated Na/k-atpase Signaling Complex Interacts Wimentioning

confidence: 99%

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Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex

Yuan

Cai

Tian

et al. 2005

MBoC

202

209

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We have shown that the caveolar Na/K-ATPase transmits ouabain signals via multiple signalplexes. To obtain the information on the composition of such complexes, we separated the Na/K-ATPase from the outer medulla of rat kidney into two different fractions by detergent treatment and density gradient centrifugation. Analysis of the light fraction indicated that both PLC-␥1 and IP3 receptors (isoforms 2 and 3, IP3R2 and IP3R3) were coenriched with the Na/K-ATPase, caveolin-1 and Src. GST pulldown assays revealed that the central loop of the Na/K-ATPase ␣1 subunit interacts with PLC-␥1, whereas the N-terminus binds IP3R2 and IP3R3, suggesting that the signaling Na/K-ATPase may tether PLC-␥1 and IP3 receptors together to form a Ca 2؉ -regulatory complex. This notion is supported by the following findings.

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Section: Regulation Of Plc-␥1 and Ip3r2 By The Activated Na/katpase Smentioning

confidence: 83%

Section: Ouabain-activated Na/k-atpase Signaling Complex Interacts Wimentioning

confidence: 99%

Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex

Yuan

Cai

Tian

et al. 2005

MBoC

202

209

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“…Several processes contribute to the spatial and temporal dynamics of Ca 2+ , such as diffusion and buffering, exchange with the extracellular space, and uptake and release from intracellular stores. The inositol 1,4,5-trisphosphate receptor (IP 3 R) ion channel is a key component in shaping Ca 2+ signals, as it controls the local efflux from the endoplasmic reticulum (ER), where Ca 2+ is sequestered at high concentration (5,6). The IP 3 R is a ligand-gated channel, subject to regulation by binding of IP 3 and also Ca 2+ itself.…”

mentioning

confidence: 99%

Emergence of ion channel modal gating from independent subunit kinetics

Bicknell

Goodhill

2016

Proc. Natl. Acad. Sci. U.S.A.

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Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca2+ concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown. Although ion channels are composed of protein subunits, previous mathematical models of modal gating are coarse grained at the level of whole-channel states, limiting further dialogue between theory and experiment. Here we propose an origin for modal gating, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level. We find good agreement with experimental data over a wide range of ligand concentrations, accounting for equilibrium channel properties, transient responses to changing ligand conditions, and modal gating statistics. We show how this can be understood within a simple analytical framework and confirm our results with stochastic simulations. The model assumes that channel subunits are independent, demonstrating that cooperative binding or concerted conformational changes are not required for modal gating. Moreover, the model embodies a generally applicable principle: If a timescale separation exists in the kinetics of individual subunits, then modal gating can arise as an emergent property of channel behavior.

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“…It has been reported that the short distance between Cys160 and Cys212 in domain b suggests a strong potential to form a covalent linkage and is likely to be present in vivo (Patterson et al, 2004). The disulphide bond of ERp44 may be important for inhibition of IP 3 Rs activity by blocking free thiol groups in the L3V domain of IP 3 Rs (Higo et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

“…There are two major types of intracellular calcium release channels or receptors, rynaodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP 3 Rs), located on sarcoplasmic reticulum (SR) or ER and nuclear membrane. Upon binding to IP 3 , IP 3 Rs release Ca 2+ to integrate signals from numerous small molecules and proteins and modulate diverse cellular functions (Patterson et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

ERp44 C160S/C212S mutants regulate IP3R1 channel activity

Pan¹,

Zheng²,

Wu³

et al. 2011

Protein Cell

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Previous studies have indicated that ERp44 inhibits inositol 1,4,5-trisphosphate (IP 3 )-induced Ca 2+ release (IICR) via IP 3 R 1 , but the mechanism remains largely unexplored. Using extracellular ATP to induce intracellular calcium transient as an IICR model, Ca 2+ image, pull down assay, and Western blotting experiments were carried out in the present study. We found that extracellular ATP induced calcium transient via IP 3 Rs (IICR) and the IICR were markedly decreased in ERp44 overexpressed Hela cells. The inhibitory effect of C160S/ C212S but not C29S/T396A/ΔT(331-377) mutants of ERp44 on IICR were significantly decreased compared with ERp44. However, the binding capacity of ERp44 to L3V domain of IP 3 R 1 (1L3V) was enhanced by ERp44 C160S/C212S mutation. Taken together, these results suggest that the mutants of ERp44, C160/C212, can more tightly bind to IP 3 R 1 but exhibit a weak inhibition of IP 3 R 1 channel activity in Hela cells.

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Inositol 1,4,5-Trisphosphate Receptors as Signal Integrators

Cited by 412 publications

References 179 publications

Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex

Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex

Emergence of ion channel modal gating from independent subunit kinetics

ERp44 C160S/C212S mutants regulate IP3R1 channel activity

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