The Ins(1,4,5)P3 regioisomers, Ins(1,4,6)P3 and Ins(1,3,6)P3, which can mimic the 1,4,5-arrangement on the inositol ring of Ins(1,4,5)P3, were examined for Ca2+ release by using four types of saponin-permeabilized cell possessing various abundances of receptor subtypes, with special reference to the relation of potency to receptor subtype. Ins(1,4,6)P3 and Ins(1,3,6)P3 were weak agonists in rat basophilic leukaemic cells (RBL cells), which possess predominantly subtype II receptors, with respective potencies of 1/200 and less than 1/500 that of Ins(1,4,5)P3 [the EC50 values were 0.2, 45 and more than 100 μM for Ins(1,4,5)P3, Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively]. Similar rank order potencies were also evaluated for the displacement of [3H]Ins(1,4,5)P3 bound to RBL cell membranes by these regioisomers. However, they caused Ca2+ release from GH3 rat pituitary cells possessing predominantly subtype I receptors more potently; Ins(1,4,6)P3 and Ins(1,3,6)P3 evoked release at respective concentrations of only one-third and one-twentieth that of Ins(1,4,5)P3 (the EC50 values were 0.4, 1.2 and 8 μM for Ins(1,4,5)P3, Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively). In COS-1 African green-monkey kidney cells, with the relative abundances of 37% of the subtype II and of 62% of the subtype III receptor, potencies of 1/40 and approx. 1/200 for Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively were exhibited relative to Ins(1,4,5)P3 (the EC50 values were 0.4, 15 and approx. 80 μM for Ins(1,4,5)P3, Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively). In HL-60 human leukaemic cells, in spite of the dominant presence of subtype I receptors (71%), similar respective potencies to those seen with COS-1 cells were exhibited (the EC50 values were 0.3, 15 and approx. 100 μM for Ins(1,4,5)P3, Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively). These results indicate that these regioisomers are the first ligands that distinguish between receptor subtypes; the present observations are of significance for the future design of molecules with enhanced selectivity.
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November 1997
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Research Article|
November 15 1997
Inositol 1,4,5-trisphosphate receptor subtypes differentially recognize regioisomers of D-myo-inositol 1,4,5-trisphosphate
Masato HIRATA;
Masato HIRATA
1
*Department of Biochemistry, Faculty of Dentistry, Kyushu University, Fukuoka 812-82, Japan
1To whom correspondence should be addressed.
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Hiroshi TAKEUCHI;
Hiroshi TAKEUCHI
*Department of Biochemistry, Faculty of Dentistry, Kyushu University, Fukuoka 812-82, Japan
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M. Andrew RILEY;
M. Andrew RILEY
†Department of Medicinal Chemistry, School of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.
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J. Stephen MILLS;
J. Stephen MILLS
†Department of Medicinal Chemistry, School of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.
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Yutaka WATANABE;
Yutaka WATANABE
‡Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790, Japan
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V. L. Barry POTTER
V. L. Barry POTTER
†Department of Medicinal Chemistry, School of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.
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Publisher: Portland Press Ltd
Received:
April 25 1997
Revision Received:
June 24 1997
Accepted:
July 14 1997
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1997
1997
Biochem J (1997) 328 (1): 93–98.
Article history
Received:
April 25 1997
Revision Received:
June 24 1997
Accepted:
July 14 1997
Citation
Masato HIRATA, Hiroshi TAKEUCHI, M. Andrew RILEY, J. Stephen MILLS, Yutaka WATANABE, V. L. Barry POTTER; Inositol 1,4,5-trisphosphate receptor subtypes differentially recognize regioisomers of D-myo-inositol 1,4,5-trisphosphate. Biochem J 15 November 1997; 328 (1): 93–98. doi: https://doi.org/10.1042/bj3280093
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