title: The novel Ins(1,4,5)P3 analogue 3-amino-3-deoxy-Ins(1,4,5)P3: a pH-dependent Ins(1,4,5)P3 receptor partial agonist in SH-SY5Y neuroblastoma cells.
abstract: We have synthesized the first amino-substituted inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] analogue, D-3-amino-3-deoxy-myo-Ins(1,4,5)P3 (9). Although 9 is a full agonist at the Ca2+ mobilizing Ins(1,4,5)P3 receptor at pH 7.2 and 7.6, it is apparently a high intrinsic activity partial agonist at pH 6.8, releasing only 80% of the Ins(1,4,5)P3-sensitive Ca2+ stores of SH-SY5Y cells. Additionally, 9 was able to fully displace [3H]Ins(1,4,5)P3 from binding sites in rat cerebellum membranes at both pH 6.8 and 7.6, indicating a full interaction with the Ins(1,4,5)P3 receptor. The activity displayed by this amino analogue is unexpected and may be indicative of a pH-dependent conformational change in the amino acid residues comprising the Ins(1,4,5)P3 binding site.
authors.affiliation: Neurochemistry Research, Mayo Foundation for Medical Education and Research, Jacksonville, Florida 32224.
authors.forename: A P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: A H
authors.initials: AH
authors.lastname: Fauq
authors.forename: R A
authors.initials: RA
authors.lastname: Wilcox
authors.forename: R A
authors.initials: RA
authors.lastname: Challiss
authors.forename: S R
authors.initials: SR
authors.lastname: Nahorski
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D015544:Inositol 1,4,5-Trisphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009447:Neuroblastoma / Q000378:metabolism*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C086550:3-amino-3-deoxy-myo-inositol 1,4,5-trisphosphate; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium