New developments in the molecular pharmacology of the myo-inositol 1,4,5-trisphosphate receptor.
Receptor-mediated activation of phospholipase C to generate inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] is a ubiquitous signalling pathway in mammalian systems. A family of three IP3 receptor subtype monomers form functional tetramers, which act as effectors for Ins(1,4,5)P3, providing a ligand-gated channel that allows Ca2+ ions to move between cellular compartments. As IP3 receptors are located principally, although not exclusively, in the endoplasmic reticular membrane, Ins(1,4,5)P3 is considered to be a second messenger that mobilizes Ca2+ from intracellular stores. Ca2+ store mobilization by Ins(1,4,5)P3 can be shown to contribute to a variety of physiological and pathophysiological phenomena, and therefore the IP3 receptor represents a novel, potential pharmacological target. In this article, Rob Wilcox and colleagues review recent developments in IP3 receptor pharmacology, with particular emphasis on ligand molecular recognition by this receptor-channel complex. The potential for designing non-inositol phosphate-based agonists and antagonists is also discussed.
Wilcox
R A
RA
School of Medicine, Flinders University, Adelaide, Australia.
Primrose
W U
WU
Nahorski
S R
SR
Challiss
R A
RA
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000031:analogs & derivatives*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate