Cooperative activation of IP3 receptors by sequential binding of IP3 and Ca2+ safeguards against spontaneous activity

Marchant, Jonathan S.; Taylor, Colin W.

doi:10.1016/s0960-9822(06)00222-3

Cited by 149 publications

(185 citation statements)

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“…This simple model was later elaborated to include at least three different Ca 2þ sensors ), but at the core of this revised scheme is a single Ca 2þ -binding site that switches from being inhibitory in the absence of IP 3 to stimulatory in its presence . The essential feature of this scheme is consistent with our initial model, derived from rapid superfusion analysis, which suggests that IP 3 both relieves Ca 2þ inhibition and promotes binding of Ca 2þ to a stimulatory site (Marchant and Taylor 1997;Adkins and Taylor 1999). The latter is essential for the channel to open.…”

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipsupporting

confidence: 82%

“…The current consensus is that binding of IP 3 to the IP 3 R is essential for its activation, but whether all four IP 3 -binding sites of the tetrameric IP 3 R must be occupied is unresolved. Positively cooperative responses to IP 3 in some (Dufour et al 1997;Marchant and Taylor 1997;Tu et al 2005a), though not all, studies (Finch et al 1991;Watras et al 1991;Laude et al 2005), and delays before the first response to IP 3 that decrease with increasing IP 3 concentration (Marchant and Taylor 1997), indicate that channel opening requires occupancy of more than one IP 3 -binding site. However, gating by IP 3 of heteromeric IP 3 R in which at least one subunit is mutated to prevent IP 3 binding suggests that occupancy of fewer than four IP 3 -binding sites may be sufficient to cause some channel opening (Boehning and Joseph 2000a).…”

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipmentioning

confidence: 94%

“…Activation of IP 3 R requires both IP 3 and its permeating ion, Ca 2þ (Finch et al 1991;Marchant and Taylor 1997;Adkins and Taylor 1999;Taylor and Laude 2002;Foskett et al 2007). There are reports of IP 3 -independent activation of IP 3 R by CaBP1 (Yang et al 2002), a member of the neuronal Ca 2þ -sensor family, and by Gbg subunits (Zeng et al 2003), but the physiological relevance is unclear (Haynes et al 2004;Nadif Kasri et al 2004).…”

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipmentioning

confidence: 99%

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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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Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipsupporting

confidence: 82%

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipmentioning

confidence: 94%

Section: Regulation Of Ip 3 Receptors By Ca 2þ and Ipmentioning

confidence: 99%

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IP3 Receptors: Toward Understanding Their Activation

Taylor¹,

Tovey²

2010

Cold Spring Harbor Perspectives in Biology

264

190

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“…This mechanism of dual-ligand regulation of the IP 3 R channel has attracted considerable interest, but the molecular dynamics underpinning this mechanism of IP 3 R channel gating is still controversial. Marchant and Taylor (13) (15,16). However, whether E2100 is involved in the IP 3 -induced high-affinity Ca 2+ binding site (13) or in one of three Ca 2+ binding sites (14) is not known.…”

mentioning

confidence: 99%

Mechanistic basis of bell-shaped dependence of inositol 1,4,5-trisphosphate receptor gating on cytosolic calcium

Shinohara

Michikawa

Enomoto

et al. 2011

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

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The inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) is an intracellular Ca 2+ release channel, and its opening is controlled by IP 3 and Ca 2+ . A single IP 3 binding site and multiple Ca 2+ binding sites exist on single subunits, but the precise nature of the interplay between these two ligands in regulating biphasic dependence of channel activity on cytosolic Ca 2+ is unknown. In this study, we visualized conformational changes in IP 3 R evoked by various concentrations of ligands by using the FRET between two fluorescent proteins fused to the N terminus of individual subunits. IP 3 and Ca 2+ have opposite effects on the FRET signal change, but the combined effect of these ligands is not a simple summative response. The bell-shaped Ca 2+ dependence of FRET efficiency was observed after the subtraction of the component corresponding to the FRET change evoked by Ca 2+ alone from the FRET changes evoked by both ligands together. A mutant IP 3 R containing a single amino acid substitution at K508, which is critical for IP 3 binding, did not exhibit this bell-shaped Ca 2+ dependence of the subtracted FRET efficiency. Mutation at E2100, which is known as a Ca 2+ sensor, resulted in w10-fold reduction in the Ca 2+ dependence of the subtracted signal. These results suggest that the subtracted FRET signal reflects IP 3 R activity. We propose a five-state model, which implements a dual-ligand competition response without complex allosteric regulation of Ca 2+ binding affinity, as the mechanism underlying the IP 3 -dependent regulation of the bell-shaped relationship between the IP 3 R activity and cytosolic Ca 2+ .calcium signal | channel gating | ion channel T he inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R) is a dualligand-gated Ca 2+ release channel whose opening is controlled by IP 3 and Ca 2+ (1) and which plays a crucial role in the generation of Ca 2+ signals that control numerous cellular processes (2). Individual IP 3 R subunits possess a single IP 3 binding site (3) and multiple Ca 2+ binding sites (4, 5), and tetrameric complexes of these subunits form functional IP 3 -gated Ca 2+ release channels (6). Cytoplasmic Ca 2+ regulates IP 3 R in a biphasic manner: Ca 2+ release is potentiated at low Ca 2+ concentrations but inhibited at higher Ca 2+ concentrations (7,8). The stimulatory effect suggests that the channels display the process of Ca 2+ -induced Ca 2+ release, which underlies Ca 2+ spike generation and wave propagation. In other words, the bell-shaped dependence on cytosolic Ca 2+ is the fundamental property of IP 3 R for the generation of Ca 2+ excitability (9).IP 3 monotonically activates the IP 3 R channels at constant Ca 2+ concentrations (10), but IP 3 dynamically changes the Ca 2+ sensitivity of the channel (11,12). At subsaturating concentrations of IP 3 , the optimal Ca 2+ concentration for IP 3 R modulation becomes lower, whereas at very high concentrations of IP 3 , channel activity persists at supramicromolar Ca 2+ concentrations (11,12). This mechanism of dual-ligand regulat...

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“…IP 3 binding is certainly accompanied by a large conformational change in the receptor (15), but the linkage between IP 3 binding and channel opening is complex. It is likely that several of the receptor subunits must first bind IP 3 and then Ca 2ϩ before the pore opens (16). Detailed structural information is required to test the predictions arising from biochemical and physiological studies to understand the gating, modulation, and ion selectivity of the IP 3 R. Here we present the 3D map of this membrane receptor, which we discuss in terms of domain distribution and its relation with other known ion-channel structures.…”

mentioning

confidence: 99%

Domain organization of the type 1 inositol 1,4,5-trisphosphate receptor as revealed by single-particle analysis

Fonseca¹,

Morris²,

Nerou³

et al. 2003

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

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Materials and Methods Purification of IP3R.A membrane fraction was prepared from rat cerebella (17), resuspended (50 mg͞ml in 50 mM Tris͞1 mM EDTA, pH 8.3), and solubilized by the addition of 1% Triton X-100. After centrifugation (100,000 ϫ g for 60 min), the supernatant, supplemented with 250 mM NaCl, was loaded onto an Econopac heparin column (1 ml, Bio-Rad), washed with 25 ml of medium A (50 mM Tris͞250 mM NaCl͞10% glycerol, pH 8.3), supplemented with 1 mM EDTA, 1% Surfact-Amps X-100 (Pierce), and then with medium A supplemented with 0.1% Surfact-Amps X-100 (50 ml). IP 3 R was eluted from the heparin column directly onto a 2-ml Con A-agarose column (Sigma) by using medium A supplemented with 0.1% Surfact-Amps X-100 and 50 M decavanadate (18). After washing with 150 ml of medium B (50 mM Tris͞100 mM NaCl͞10% glycerol͞0.1% Surfact-Amps X-100, pH 8.3), IP 3 R was eluted by overnight incubation with 4 ml of medium B containing 800 mM methyl mannopyranoside (17). To assess the quaternary structure of the purified receptor, 0.2-ml fractions of the final eluate were loaded onto linear 10-30% sucrose gradients (10 ml) in 50 mM Tris͞1 mM EDTA͞0.1% Surfact-Amps X-100, pH 8.3, and centrifuged (134,000 ϫ g for 60 min). Gradients were calibrated by using a high-molecular-weight gel filtration standards kit (Amersham Biosciences). Size-exclusion HPLC was preformed by using a Zorbax GF-450 column (Jones Chromatography, Lakewood, CO) coupled to a Kontron system (Kontron Instruments, Watford, U.K.). All media included the following mixture of protease inhibitors: 150 nM aprotinin, 1 M pepstatin, 20 g͞ml soybean trypsin inhibitor, 1 mM benzamidine, 250 M PMSF, 250 M captopril, and 1 M bestatin.

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Cooperative activation of IP3 receptors by sequential binding of IP3 and Ca2+ safeguards against spontaneous activity

Cited by 149 publications

References 44 publications

IP3 Receptors: Toward Understanding Their Activation

IP3 Receptors: Toward Understanding Their Activation

Mechanistic basis of bell-shaped dependence of inositol 1,4,5-trisphosphate receptor gating on cytosolic calcium

Domain organization of the type 1 inositol 1,4,5-trisphosphate receptor as revealed by single-particle analysis

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