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      Selective determinants of inositol 1,4,5-trisphosphate and adenophostin A interactions with type 1 inositol 1,4,5-trisphosphate receptors

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          Abstract

          BACKGROUND AND PURPOSE

          Adenophostin A (AdA) is a potent agonist of inositol 1,4,5-trisphosphate receptors (IP 3R). AdA shares with IP 3 the essential features of all IP 3R agonists, namely structures equivalent to the 4,5-bisphosphate and 6-hydroxyl of IP 3, but the basis of its increased affinity is unclear. Hitherto, the 2′-phosphate of AdA has been thought to provide a supra-optimal mimic of the 1-phosphate of IP 3.

          EXPERIMENTAL APPROACH

          We examined the structural determinants of AdA binding to type 1 IP 3R (IP 3R1). Chemical synthesis and mutational analysis of IP 3R1 were combined with 3H-IP 3 binding to full-length IP 3R1 and its N-terminal fragments, and Ca 2+ release assays from recombinant IP 3R1 expressed in DT40 cells.

          KEY RESULTS

          Adenophostin A is at least 12-fold more potent than IP 3 in functional assays, and the IP 3-binding core (IBC, residues 224–604 of IP 3R1) is sufficient for this high-affinity binding of AdA. Removal of the 2′-phosphate from AdA (to give 2′-dephospho-AdA) had significantly lesser effects on its affinity for the IBC than did removal of the 1-phosphate from IP 3 (to give inositol 4,5-bisphosphate). Mutation of the only residue (R568) that interacts directly with the 1-phosphate of IP 3 decreased similarly (by ∼30-fold) the affinity for IP 3 and AdA, but mutating R504, which has been proposed to form a cation-π interaction with the adenine of AdA, more profoundly reduced the affinity of IP 3R for AdA (353-fold) than for IP 3 (13-fold).

          CONCLUSIONS AND IMPLICATIONS

          The 2′-phosphate of AdA is not a major determinant of its high affinity. R504 in the receptor, most likely via a cation-π interaction, contributes specifically to AdA binding.

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          Most cited references 49

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          Calcium signalling: dynamics, homeostasis and remodelling.

          Ca2+ is a highly versatile intracellular signal that operates over a wide temporal range to regulate many different cellular processes. An extensive Ca2+-signalling toolkit is used to assemble signalling systems with very different spatial and temporal dynamics. Rapid highly localized Ca2+ spikes regulate fast responses, whereas slower responses are controlled by repetitive global Ca2+ transients or intracellular Ca2+ waves. Ca2+ has a direct role in controlling the expression patterns of its signalling systems that are constantly being remodelled in both health and disease.
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            Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction.

             Y. Cheng,  W. Prusoff (1973)
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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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                Author and article information

                Journal
                Br J Pharmacol
                bph
                British Journal of Pharmacology
                Blackwell Publishing Ltd
                0007-1188
                1476-5381
                November 2010
                : 161
                : 5
                : 1070-1085
                Affiliations
                [1 ]simpleDepartment of Pharmacology, University of Cambridge Cambridge, UK
                [2 ]simpleWolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath Bath, UK
                Author notes
                Correspondence Colin W. Taylor, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. E-mail: cwt1000@ 123456cam.ac.uk
                [*]

                Present address: Indian Institute of Science Education and Research, Thiruvananthapuram, Kerala-695016, India.

                Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms

                10.1111/j.1476-5381.2010.00947.x
                2998688
                20977457
                Copyright © 2010 The British Pharmacological Society
                Categories
                Research Papers

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