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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Boron Compounds / pharmacology
  • Caffeine / pharmacology
  • Calcium / metabolism*
  • Cell Line
  • Chickens
  • Heparin / pharmacology*
  • Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors*
  • Macrocyclic Compounds / pharmacology
  • Oxazoles / pharmacology


  • Boron Compounds
  • Inositol 1,4,5-Trisphosphate Receptors
  • Macrocyclic Compounds
  • Oxazoles
  • xestospongin C
  • xestospongin D
  • Caffeine
  • Heparin
  • 2-aminoethoxydiphenyl borate
  • Calcium