Dynamic clustering of IP3 receptors by IP3

Rahman, Taufiq

doi:10.1042/bst20110772

Cited by 27 publications

(21 citation statements)

References 45 publications

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“…We liken this to channel clustering. Both RyRs and IP 3 Rs form clusters, and such an arrangement is thought to be important for coordinating channel activity, particularly for RyR during excitation-contraction coupling (Rahman, 2012;Schendel et al, 2012). Interestingly, a uniform increase in TPC density also has a broadening effect on the concentration-effect relationship (Fig.…”

Section: Discussionmentioning

confidence: 96%

A computational model of lysosome-ER Ca2+ microdomains

Penny

Kilpatrick

Han

et al. 2014

Journal of Cell Science

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Section: Discussionmentioning

confidence: 96%

A computational model of lysosome-ER Ca2+ microdomains

Penny

Kilpatrick

Han

et al. 2014

Journal of Cell Science

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“…5A, the average of PA in the FIPI+ FERT group was 1.22 versus 1.02 ng in the egg, but these values were not significantly different). A small amount of PA may produce a small increase in [Ca] i that would be amplified through calcium-induced calcium release which could involve [Ca] i activation of PLC (Rhee, 2001; Stith et al, 1993) or IP3 receptors (Larabell and Nuccitelli, 1992; Larabell et al, 2004; Miyazaki, 2006; Rahman, 2012; Shuai et al, 2007). As another source of PA, we have found that sperm contain PA (W. Holland and B. Stith, unpublished) and treatment of the egg with FIPI or 1-butanol would not affect sperm PA.…”

Section: Discussionmentioning

confidence: 99%

Activation of Src and release of intracellular calcium by phosphatidic acid during Xenopus laevis fertilization

Bates

Fees

Holland

et al. 2014

Developmental Biology

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We report a new step in the fertilization in Xenopus laevis which has been found to involve activation of Src tyrosine kinase to stimulate phospholipase C-γ (PLC- γ) which increases inositol 1,4,5-trisphosphate (IP3) to release intracellular calcium ([Ca]i). Molecular species analysis and mass measurements suggested that sperm activate phospholipase D (PLD) to elevate phosphatidic acid (PA). We now report that PA mass increased 2.7 fold by 1 minute after insemination and inhibition of PA production by two methods inhibited activation of Src and PLCγ, increased [Ca]i and other fertilization events. As compared to 14 other lipids, PA strongly bound Xenopus Src but not PLCγ. Addition of synthetic PA activated egg Src (an action requiring intact lipid rafts) and PLCγ as well as doubling the amount of PLCγ in rafts. In the absence of elevated [Ca]i, PA addition elevated IP3 mass to levels equivalent to that induced by sperm (but twice that achieved by calcium ionophore). Finally, PA induced [Ca]i release that was blocked by an IP3 receptor inhibitor. As only PLD1b message was detected, and Western blotting did not detect PLD2, we suggest that sperm activate PLD1b to elevate PA which then binds to and activates Src leading to PLCγ stimulation, IP3 elevation and [Ca]i release. Due to these and other studies, PA may also play a role in membrane fusion events such as sperm-egg fusion, cortical granule exocytosis, the elevation of phosphatidylinositol 4,5-bisphosphate and the large, late increase in sn 1,2-diacylglycerol in fertilization.

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“…The intervening region is referred to as the regulatory or coupling domain and structure/function studies have revealed important insights into how IP3 binding at the N-terminal region leads to channel opening in the C-terminal region (11). There is evidence to suggest that the IP3Rs are arranged in the ER membrane in a nonrandom distribution and that dynamic clustering of these receptors may be functionally important (12,13). Phosphorylation and dephosphorylation of the IP3R also regulates Ca 2+ flux through this channel (14), but it remains to be determined whether the IP3R is regulated by other posttranslational modifications.…”

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confidence: 99%

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex

Fredericks¹,

Hoffmann²,

Rose³

et al. 2014

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

134

123

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Calcium (Ca 2+ ) is a secondary messenger in cells and Ca 2+ flux initiated from endoplasmic reticulum (ER) stores via inositol 1,4,5-triphosphate (IP3) binding to the IP3 receptor (IP3R) is particularly important for the activation and function of immune cells. Previous studies demonstrated that genetic deletion of selenoprotein K (Selk) led to decreased Ca 2+ flux in a variety of immune cells and impaired immunity, but the mechanism was unclear. Here we show that Selk deficiency does not affect receptor-induced IP3 production, but Selk deficiency through genetic deletion or low selenium in culture media leads to low expression of the IP3R due to a defect in IP3R palmitoylation. Bioinformatic analysis of the DHHC (letters represent the amino acids aspartic acid, histidine, histidine, and cysteine in the catalytic domain) family of enzymes that catalyze protein palmitoylation revealed that one member, DHHC6, contains a predicted Src-homology 3 (SH3) domain and DHHC6 is localized to the ER membrane. Because Selk is also an ER membrane protein and contains an SH3 binding domain, immunofluorescence and coimmunoprecipitation experiments were conducted and revealed DHHC6/Selk interactions in the ER membrane that depended on SH3/SH3 binding domain interactions. DHHC6 knockdown using shRNA in stably transfected cell lines led to decreased expression of the IP3R and impaired IP3R-dependent Ca 2+ flux. Mass spectrophotometric and bioinformatic analyses of the IP3R protein identified two palmitoylated cysteine residues and another potentially palmitoylated cysteine, and mutation of these three cysteines to alanines resulted in decreased IP3R palmitoylation and function. These findings reveal IP3R palmitoylation as a critical regulator of Ca 2+ flux in immune cells and define a previously unidentified DHHC/Selk complex responsible for this process.I mmune cell activation relies on receptor-mediated increases in cellular calcium (Ca 2+ ) concentrations, which is an indispensable step in proliferation, differentiation, migration, and effector functions during immune responses (1, 2). A rapid influx of Ca 2+ has been shown to be important during the activation of lymphocytes through the T-and B-cell receptors, macrophages through Fcγ receptors, and mast cells through Fce receptors and stimulation of various immune cells through chemokine receptors (3). Engagement of these receptors at the plasma membrane leads to the activation of phosphoinositide-specific phospholipase C, which catalyzes the degradation of phosphatidylinositol-4,5-bisphosphate to generate inositol 1,4,5-triphosphate (IP3) and diacylglycerol (4). IP3 binds to the IP3 receptor (IP3R) in the endoplasmic reticulum (ER) membrane leading to Ca 2+ mobilization from the ER, which is the main Ca 2+ store in immune cells (5). The release of Ca 2+ from the ER lumen to the cytosol causes structural changes and oligomerization of the ER transmembrane protein, stromal interaction molecule 1 (STIM1) (6, 7). These changes allow the cytosolic domain of STIM1 to directly inte...

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Dynamic clustering of IP3 receptors by IP3

Cited by 27 publications

References 45 publications

A computational model of lysosome-ER Ca2+ microdomains

A computational model of lysosome-ER Ca2+ microdomains

Activation of Src and release of intracellular calcium by phosphatidic acid during Xenopus laevis fertilization

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex

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