The subtypes of the mouse inositol 1,4,5-trisphosphate receptor are expressed in a tissue-specific and developmentally specific manner.

Nakagawa, Toshiyuki; Okano, Hideyuki; Furuichi, Teiichi; Aruga, Jun; Mikoshiba, Katsuhiko

doi:10.1073/pnas.88.14.6244

Cited by 218 publications

(169 citation statements)

References 36 publications

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“…However, in order to fit their experimental data obtained with permeabilized basophilic leukaemia cells, they also had to assume that there are two distinct types of InsP $ receptors with different affinities, forming mixed populations of heterotetramers, and that three out of the four receptors within the tetramer need to be occupied for channel opening to occur. Such a model could also explain our data since, although 99 % of the InsP $ receptors in the cerebellum are of the type I isoform [24], both types of the splice variant within the InsP $ binding domain (S1) exist (25 % S1 + and 75 % S1 − [29]), allowing for some heterogeneity in InsP $ sensitivity in our system. The initial observation that the thiol-reactive reagent thimerosal was able to sensitize IICR in permeabilized hepatocytes [3] has provoked much interest in the effects of cysteine modification on InsP $ receptor function.…”

Section: Discussionmentioning

confidence: 73%

Effects of thimerosal on the transient kinetics of inositol 1,4,5-trisphosphate-induced Ca2+ release from cerebellar microsomes

Mezna

Michelangeli

1997

Biochemical Journal

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Thimerosal, a thiol-reactive reagent, has been shown to increase the cytosolic Ca# + concentration in a variety of cells by sensitizing inositol 1,4,5-trisphosphate (InsP $ ) receptors. Thimerosal can have both sensitizing (at concentrations of 2 µM) and inhibitory (at concentrations of 2 µM) effects on InsP $ -induced Ca# + release (IICR) from cerebellar microsomes. Transient kinetic studies were performed by employing a fluorimetric stopped-flow approach using fluo-3. IICR was found to be a biexponential process with a fast and a slow component. At a maximal InsP $ concentration (20 µM), the fast phase had a rate constant of 0.9 s −" and the slow phase had a rate constant of 0.4 s −" . The amplitudes of the two phases were 60 % and 40 % respectively. When the rate constants for the two phases were plotted as Hill plots, the processes were found to be non-co-

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Section: Discussionmentioning

confidence: 73%

Effects of thimerosal on the transient kinetics of inositol 1,4,5-trisphosphate-induced Ca2+ release from cerebellar microsomes

Mezna

Michelangeli

1997

Biochemical Journal

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“…Similar to the InsP3 type 1 receptor [11,12], new findings suggest that further heterogeneity in the RyR family may result from alternative splicings of mRNA. Two alternative splicing sites have been localized in human and mouse RyRI mRNA.…”

Section: Introductionmentioning

confidence: 79%

“…The possibility that different combinations of the alternatively spliced variants to form homo-and/or heterotetrameric channels may result in further heterogeneity in the calcium release properties of RyRs. This consideration is further supported by the characterization of the functional properties of the proteins encoded by alternatively spliced transcripts of the InsP3 receptor type 1 [11,24,25].…”

Section: Discussionmentioning

confidence: 95%

cDNA cloning reveals a tissue specific expression of alternatively spliced transcripts of the ryanodine receptor type 3 (RyR3) calcium release channel

et al. 1996

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“…We constructed and expressed a total of 26 GST fusion proteins that contain small fragments (56 -202 amino acids) of the InsP 3 R-1 in E. coli. These short fragments of the InsP 3 R covered the complete cytosolic N-terminal 2275 amino acids, including the S-I and the S-II splice domain (29) and the Cterminal 150 amino acids of the mouse InsP 3 R-1 (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Molecular and Functional Evidence for Multiple Ca2+-binding Domains in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

Sienaert

Missiaen

Smedt

et al. 1997

Journal of Biological Chemistry

138

104

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Structural and functional analyses were used to investigate the regulation of the inositol 1,4,5-trisphosphate (InsP 3 ) receptor (InsP 3 R) by Ca 2؉ . To define the structural determinants for Ca 2؉ binding, cDNAs encoding GST fusion proteins that covered the complete linear cytosolic sequence of the InsP 3 R-1 were expressed in bacteria. The fusion proteins were screened for Ca 2؉ and ruthenium red binding through the use of 45 The inositol 1,4,5-trisphosphate receptor (InsP 3 R) 1 is an intracellular Ca 2ϩ release channel that is modulated by various physiological ligands such as inositol 1,4,5-trisphosphate (InsP 3 ), Ca 2ϩ , nucleotides, calmodulin (CaM), FK506BP, phosphatases, and kinases (reviewed in Refs. 1 and 2). The InsP 3 R can be divided into three functionally different domains as follows: an N-terminal ligand-binding domain, a modulatory domain, and a channel domain near the C terminus (3, 4). Among the various modulators, Ca 2ϩ itself plays a pivotal role and may be considered as a co-agonist exerting both positive and negative effects on InsP 3 -induced Ca 2ϩ release. Cytosolic Ca 2ϩ has a bell-shaped effect on the InsP 3 R, with low concentrations stimulating the release and high concentrations inhibiting the release (5-8). Both phases are time-dependent, but the inhibition develops more slowly than the stimulation (6, 9 -11). Although these kinetically distinct effects are believed to be crucial for the generation of Ca 2ϩ oscillations and waves (12), little is known about how Ca 2ϩ interacts with the InsP 3 R. Regulation might be exerted by direct binding of Ca 2ϩ to the InsP 3 R and/or via Ca 2ϩ -sensitive protein(s), e.g. via Ca 2ϩ /CaMdependent protein kinase II and protein phosphatase 2B (13) or via a Ca 2ϩ -sensitizing factor (14). Studies in which effects of Sr 2ϩ were compared with those of Ca 2ϩ revealed that at least two interaction sites must exist: a stimulatory site that is modestly sensitive to Sr 2ϩ and an inhibitory site that is nearly insensitive to Sr 2ϩ (15). One Ca 2ϩ -binding domain has been localized on the cytosolic side of the InsP 3 R-1 (16, 17), but whether this domain represents a stimulatory or an inhibitory interaction site is still unclear. Luminal Ca 2ϩ also regulates the InsP 3 -induced Ca 2ϩ release. Loading of the Ca 2ϩ stores results in a relatively more pronounced InsP 3 -induced Ca 2ϩ release (18 -21). A high affinity Ca 2ϩ -binding site was detected on the luminal loop (17), but its functional significance is not yet clear.The aim of the present work was two-fold. First, we wanted to investigate, at the structural level, the presence of direct Ca 2ϩ -binding sites on InsP 3 R-1. Second, we wanted to functionally demonstrate multiple Ca 2ϩ interactions on the InsP 3 R by a kinetic analysis of the effects of Ca 2ϩ and Sr 2ϩ on the InsP 3 -induced Ca 2ϩ release.For the first part of this study we constructed and expressed a number of GST fusion proteins that contain cytosolic fragments of the InsP 3 R sequence. The ability of these fusion proteins to bind ...

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The subtypes of the mouse inositol 1,4,5-trisphosphate receptor are expressed in a tissue-specific and developmentally specific manner.

Cited by 218 publications

References 36 publications

Effects of thimerosal on the transient kinetics of inositol 1,4,5-trisphosphate-induced Ca2+ release from cerebellar microsomes

Effects of thimerosal on the transient kinetics of inositol 1,4,5-trisphosphate-induced Ca2+ release from cerebellar microsomes

cDNA cloning reveals a tissue specific expression of alternatively spliced transcripts of the ryanodine receptor type 3 (RyR3) calcium release channel

Molecular and Functional Evidence for Multiple Ca2+-binding Domains in the Type 1 Inositol 1,4,5-Trisphosphate Receptor

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