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Br J Pharmacol. 2014 Jul;171(13):3298-312. doi: 10.1111/bph.12685.

Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate (IP3) receptor.

Author information

1
Department of Pharmacology, University of Cambridge, Cambridge, UK.

Abstract

BACKGROUND AND PURPOSE:

Inositol 1,4,5-trisphosphate receptors (IP3 Rs) are intracellular Ca(2+) channels. Interactions of the commonly used antagonists of IP3Rs with IP3R subtypes are poorly understood.

EXPERIMENTAL APPROACH:

IP3-evoked Ca(2+) release from permeabilized DT40 cells stably expressing single subtypes of mammalian IP3R was measured using a luminal Ca(2+) indicator. The effects of commonly used antagonists on IP3-evoked Ca(2+) release and (3) H-IP3 binding were characterized.

KEY RESULTS:

Functional analyses showed that heparin was a competitive antagonist of all IP3R subtypes with different affinities for each (IP3R3 > IP3R1 ≥ IP3R2). This sequence did not match the affinities for heparin binding to the isolated N-terminal from each IP3R subtype. 2-aminoethoxydiphenyl borate (2-APB) and high concentrations of caffeine selectively inhibited IP3R1 without affecting IP3 binding. Neither Xestospongin C nor Xestospongin D effectively inhibited IP3-evoked Ca(2+) release via any IP3R subtype.

CONCLUSIONS AND IMPLICATIONS:

Heparin competes with IP3, but its access to the IP3-binding core is substantially hindered by additional IP3R residues. These interactions may contribute to its modest selectivity for IP3R3. Practicable concentrations of caffeine and 2-APB inhibit only IP3R1. Xestospongins do not appear to be effective antagonists of IP3Rs.

KEYWORDS:

2-APB; Ca2+ signal; DT40 cell; IP3 receptor; Xestospongin; antagonist; caffeine; heparin; inositol 1,4,5-trisphosphate; structure-activity relationship

PMID:
24628114
PMCID:
PMC4080982
DOI:
10.1111/bph.12685
[Indexed for MEDLINE]
Free PMC Article

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