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      Stimulation of Inositol 1,4,5-Trisphosphate (IP 3) Receptor Subtypes by Analogues of IP 3

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          Abstract

          Most animal cells express mixtures of the three subtypes of inositol 1,4,5-trisphosphate receptor (IP 3R) encoded by vertebrate genomes. Activation of each subtype by different agonists has not hitherto been examined in cells expressing defined homogenous populations of IP 3R. Here we measure Ca 2+ release evoked by synthetic analogues of IP 3 using a Ca 2+ indicator within the lumen of the endoplasmic reticulum of permeabilized DT40 cells stably expressing single subtypes of mammalian IP 3R. Phosphorylation of (1,4,5)IP 3 to (1,3,4,5)IP 4 reduced potency by ∼100-fold. Relative to (1,4,5)IP 3, the potencies of IP 3 analogues modified at the 1-position (malachite green (1,4,5)IP 3), 2-position (2-deoxy(1,4,5)IP 3) or 3-position (3-deoxy(1,4,5)IP 3, (1,3,4,5)IP 4) were similar for each IP 3R subtype. The potency of an analogue, (1,4,6)IP 3, in which the orientations of the 2- and 3-hydroxyl groups were inverted, was also reduced similarly for all three IP 3R subtypes. Most analogues of IP 3 interact similarly with the three IP 3R subtypes, but the decrease in potency accompanying removal of the 1-phosphate from (1,4,5)IP 3 was least for IP 3R3. Addition of a large chromophore (malachite green) to the 1-phosphate of (1,4,5)IP 3 only modestly reduced potency suggesting that similar analogues could be used to measure (1,4,5)IP 3 binding optically. These data provide the first structure-activity analyses of key IP 3 analogues using homogenous populations of each mammalian IP 3R subtype. They demonstrate broadly similar structure-activity relationships for all mammalian IP 3R subtypes and establish the potential utility of (1,4,5)IP 3 analogues with chromophores attached to the 1-position.

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          Most cited references41

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          Inositol trisphosphate receptor Ca2+ release channels.

          The inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3Rs) are a family of Ca2+ release channels localized predominately in the endoplasmic reticulum of all cell types. They function to release Ca2+ into the cytoplasm in response to InsP3 produced by diverse stimuli, generating complex local and global Ca2+ signals that regulate numerous cell physiological processes ranging from gene transcription to secretion to learning and memory. The InsP3R is a calcium-selective cation channel whose gating is regulated not only by InsP3, but by other ligands as well, in particular cytoplasmic Ca2+. Over the last decade, detailed quantitative studies of InsP3R channel function and its regulation by ligands and interacting proteins have provided new insights into a remarkable richness of channel regulation and of the structural aspects that underlie signal transduction and permeation. Here, we focus on these developments and review and synthesize the literature regarding the structure and single-channel properties of the InsP3R.
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            Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44.

            Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are intracellular channel proteins that mediate Ca(2+) release from the endoplasmic reticulum (ER) and are involved in many biological processes and diseases. IP(3)Rs are differentially regulated by a variety of cytosolic proteins, but their regulation by ER lumenal protein(s) remains largely unexplored. In this study, we found that ERp44, an ER lumenal protein of the thioredoxin family, directly interacts with the third lumenal loop of IP(3)R type 1 (IP(3)R1) and that the interaction is dependent on pH, Ca(2+) concentration, and redox state: the presence of free cysteine residues in the loop is required. Ca(2+)-imaging experiments and single-channel recording of IP(3)R1 activity with a planar lipid bilayer system demonstrated that IP(3)R1 is directly inhibited by ERp44. Thus, ERp44 senses the environment in the ER lumen and modulates IP(3)R1 activity accordingly, which should in turn contribute to regulating both intralumenal conditions and the complex patterns of cytosolic Ca(2+) concentrations.
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              Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-trisphosphate receptor.

              The inositol 1,4,5-trisphosphate (InsP3) receptor acts as an InsP3-gated Ca2+ release channel in a variety of cell types. Type 1 InsP3 receptor (IP3R1) is the major neuronal member of the IP3R family in the central nervous system, predominantly enriched in cerebellar Purkinje cells but also concentrated in neurons in the hippocampal CA1 region, caudate-putamen, and cerebral cortex. Here we report that most IP3R1-deficient mice generated by gene targeting die in utero, and born animals have severe ataxia and tonic or tonic-clonic seizures and die by the weaning period. An electroencephalogram showed that they suffer from epilepsy, indicating that IP3R1 is essential for proper brain function. However, observation by light microscope of the haematoxylin-eosin staining of the brain and peripheral tissues of IP3R1-deficient mice showed no abnormality, and the unique electrophysiological properties of the cerebellar Purkinje cells of IP3R1-deficient mice were not severely impaired.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                25 January 2013
                : 8
                : 1
                : e54877
                Affiliations
                [1 ]Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
                [2 ]Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom
                Medical School of Hannover, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CWT SCT BVLP AMR. Performed the experiments: HS TR. Analyzed the data: HS CWT SCT. Contributed reagents/materials/analysis tools: BVLP AMR. Wrote the paper: CWT HS SCT TR AMR BVLP.

                Article
                PONE-D-12-32681
                10.1371/journal.pone.0054877
                3556037
                23372785
                bf7e6881-86ec-48da-b0dd-2df64a53f6e5
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 October 2012
                : 17 December 2012
                Page count
                Pages: 14
                Funding
                This work was supported by grants from the Wellcome Trust to CWT [085295], and BVLP and AMR [082837], and from Biotechnology and Biological Sciences Research Council to CWT [BB/H009736/1]. HS is supported by a research studentship from the Jameel Family Trust. TR was a research fellow of Pembroke College, Cambridge. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Cell Physiology
                Biochemistry
                Proteins
                Ion Channels
                Chemical Biology
                Biophysics
                Biomacromolecule-Ligand Interactions
                Molecular Cell Biology
                Signal Transduction
                Signaling in Cellular Processes
                Calcium Signaling
                Medicine
                Drugs and Devices
                Pharmacodynamics

                Uncategorized
                Uncategorized

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