Three-dimensional structure of recombinant type 1 inositol 1,4,5-trisphosphate receptor

Wolfram, F.; Morris, Edward P.; Taylor, Colin W.

doi:10.1042/bj20100143

Cited by 18 publications

(14 citation statements)

References 44 publications

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“…Using image reconstructions based on electron cryomicroscopy or electron microscopy with negative staining, 3-D structures of single tetrameric InsP 3 R channel have been determined (Jiang et al, 2002; da Fonseca et al, 2003; Hamada et al, 2003; Serysheva et al, 2003; Sato et al, 2004; Wolfram et al, 2010; Ludtke et al, 2011). Although the details differ significantly, they generally show a large structure on the cytoplasmic side with maximum radius ( r ) from the channel pore axis between 10.5 and 14.2 nm, and height above the ER membrane ( h ) between 13.5 and 18.3 nm.…”

Section: Discussionmentioning

confidence: 99%

“…The [Ca 2+ ] i profile around an open InsP 3 R channel was calculated by considering the open channel as a circular aqueous pore with a diameter of 2.5 nm (Jiang et al, 2002; Serysheva et al, 2003; Wolfram et al, 2010). Magnitudes of the Ca 2+ current through an open channel ( i Ca ) in the presence of 140 mM KCl and various [Ca 2+ ] i , [Ca 2+ ] ER , and V app were evaluated using the general Goldman–Hodgkin–Katz current equation (Lewis, 1979; Hille, 2001):…”

Section: Methodsmentioning

confidence: 99%

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Permeant calcium ion feed-through regulation of single inositol 1,4,5-trisphosphate receptor channel gating

Vais

Foskett

Ullah

et al. 2012

Journal of General Physiology

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The ubiquitous inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) Ca2+ release channel plays a central role in the generation and modulation of intracellular Ca2+ signals, and is intricately regulated by multiple mechanisms including cytoplasmic ligand (InsP3, free Ca2+, free ATP4−) binding, posttranslational modifications, and interactions with cytoplasmic and endoplasmic reticulum (ER) luminal proteins. However, regulation of InsP3R channel activity by free Ca2+ in the ER lumen ([Ca2+]ER) remains poorly understood because of limitations of Ca2+ flux measurements and imaging techniques. Here, we used nuclear patch-clamp experiments in excised luminal-side-out configuration with perfusion solution exchange to study the effects of [Ca2+]ER on homotetrameric rat type 3 InsP3R channel activity. In optimal [Ca2+]i and subsaturating [InsP3], jumps of [Ca2+]ER from 70 nM to 300 µM reduced channel activity significantly. This inhibition was abrogated by saturating InsP3 but restored when [Ca2+]ER was raised to 1.1 mM. In suboptimal [Ca2+]i, jumps of [Ca2+]ER (70 nM to 300 µM) enhanced channel activity. Thus, [Ca2+]ER effects on channel activity exhibited a biphasic dependence on [Ca2+]i. In addition, the effect of high [Ca2+]ER was attenuated when a voltage was applied to oppose Ca2+ flux through the channel. These observations can be accounted for by Ca2+ flux driven through the open InsP3R channel by [Ca2+]ER, raising local [Ca2+]i around the channel to regulate its activity through its cytoplasmic regulatory Ca2+-binding sites. Importantly, [Ca2+]ER regulation of InsP3R channel activity depended on cytoplasmic Ca2+-buffering conditions: it was more pronounced when [Ca2+]i was weakly buffered but completely abolished in strong Ca2+-buffering conditions. With strong cytoplasmic buffering and Ca2+ flux sufficiently reduced by applied voltage, both activation and inhibition of InsP3R channel gating by physiological levels of [Ca2+]ER were completely abolished. Collectively, these results rule out Ca2+ regulation of channel activity by direct binding to the luminal aspect of the channel.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Permeant calcium ion feed-through regulation of single inositol 1,4,5-trisphosphate receptor channel gating

Vais

Foskett

Ullah

et al. 2012

Journal of General Physiology

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“…2B). Whether structures of recombinant IP 3 R will contribute to resolving this impasse remains to be seen (Wolfram et al 2010). …”

Section: Structural Determinants Of Ip 3 R Activationmentioning

confidence: 99%

IP3 Receptors: Toward Understanding Their Activation

Taylor¹,

Tovey²

2010

Cold Spring Harbor Perspectives in Biology

264

190

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Inositol 1,4,5-trisphosphate receptors (IP 3 R) and their relatives, ryanodine receptors, are the channels that most often mediate Ca 2þ release from intracellular stores. Their regulation by Ca 2þ allows them also to propagate cytosolic Ca 2þ signals regeneratively. This brief review addresses the structural basis of IP 3 R activation by IP 3 and Ca 2þ . IP 3 initiates IP 3 R activation by promoting Ca 2þ binding to a stimulatory Ca 2þ -binding site, the identity of which is unresolved. We suggest that interactions of critical phosphate groups in IP 3 with opposite sides of the clam-like IP 3 -binding core cause it to close and propagate a conformational change toward the pore via the adjacent N-terminal suppressor domain. The pore, assembled from the last pair of transmembrane domains and the intervening pore loop from each of the four IP 3 R subunits, forms a structure in which a luminal selectivity filter and a gate at the cytosolic end of the pore control cation fluxes through the IP 3 R.

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“…Culture of Sf9 cells, infection with baculovirus encoding rat IP 3 R1, and preparation of membranes were as described previously. 49 Quantification of IP 3 R1 expression by Western blotting, using an anti-peptide antiserum to IP 3 R1 49 was performed as described. 50 Analysis.…”

Section: Biologymentioning

confidence: 99%

Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors

et al. 2016

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Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca(2+) channels that are widely expressed in animal cells, where they mediate the release of Ca(2+) from intracellular stores evoked by extracellular stimuli. A diverse array of synthetic agonists of IP3Rs has defined structure-activity relationships, but existing antagonists have severe limitations. We combined analyses of Ca(2+) release with equilibrium competition binding to IP3R to show that (1,3,4,6)IP4 is a full agonist of IP3R1 with lower affinity than (1,4,5)IP3. Systematic manipulation of this meso-compound via a versatile synthetic scheme provided a family of dimeric analogs of 2-O-butyryl-(1,3,4,6)IP4 and (1,3,4,5,6)IP5 that compete with (1,4,5)IP3 for binding to IP3R without evoking Ca(2+) release. These novel analogs are the first inositol phosphate-based competitive antagonists of IP3Rs with affinities comparable to that of the only commonly used competitive antagonist, heparin, the utility of which is limited by off-target effects.

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Three-dimensional structure of recombinant type 1 inositol 1,4,5-trisphosphate receptor

Cited by 18 publications

References 44 publications

Permeant calcium ion feed-through regulation of single inositol 1,4,5-trisphosphate receptor channel gating

Permeant calcium ion feed-through regulation of single inositol 1,4,5-trisphosphate receptor channel gating

IP3 Receptors: Toward Understanding Their Activation

Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors

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