The Novel Ins(1,4,5)P3 Analog 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

Alan P. Kozikowski; Abdul H. Fauq; Robert A. Wilcox; R. A.John Challiss; Stefan R. Nahorski

doi:10.1021/jm00032a022

The Novel Ins(1,4,5)P₃ Analog 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

Alan P. Kozikowski, Abdul H. Fauq, Robert A. Wilcox, R. A.John Challiss, Stefan R. Nahorski

School of Medicine

Research output: Contribution to journal › Comment/debate › peer-review

14 Scopus citations

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.

Original language	English (US)
Pages (from-to)	868-872
Number of pages	5
Journal	Journal of medicinal chemistry
Volume	37
Issue number	6
DOIs	https://doi.org/10.1021/jm00032a022
State	Published - Mar 1 1994

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Molecular Medicine
Drug Discovery

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@article{350b6df8bdc04087a170b590b43b04a6,

title = "The Novel Ins(1,4,5)P3 Analog 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.",

author = "Kozikowski, {Alan P.} and Fauq, {Abdul H.} and Wilcox, {Robert A.} and Challiss, {R. A.John} and Nahorski, {Stefan R.}",

year = "1994",

month = mar,

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doi = "10.1021/jm00032a022",

language = "English (US)",

volume = "37",

pages = "868--872",

journal = "Journal of medicinal chemistry",

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T1 - The Novel Ins(1,4,5)P3 Analog 3-Amino-3-deoxy-Ins(1,4,5)P3

T2 - A pH-Dependent Ins(1,4,5)P3 Receptor Partial Agonist in SH-SY5Y Neuroblastoma Cells

AU - Kozikowski, Alan P.

AU - Fauq, Abdul H.

AU - Wilcox, Robert A.

AU - Challiss, R. A.John

AU - Nahorski, Stefan R.

PY - 1994/3/1

Y1 - 1994/3/1

N2 - 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.

AB - 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.

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The Novel Ins(1,4,5)P₃ Analog 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

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