New developments in the molecular pharmacology of the myo-inositol 1,4,5-trisphosphate receptor

Synapse Specificity of Calcium Release Probed by Chemical Two-photon Uncaging of Inositol 1,4,5-Trisphosphate

“…1a, in which modifications to the phosphate groups at positions 1, 4, and 5 are indicated as R 1 , R 2 , and R 3 , respectively. The 4,5-biphosphate motif has been found to be necessary for IP 3 receptor activation (12,22), and modification at the 1-position has been shown to moderately affect the potency of receptor activation and strongly inhibit metabolism by 3-kinases and 5-phosphatases (23). IP 3 caged with NPE groups at either the 4 or 5 position (singlecaged IP 3 ) was synthesized or obtained commercially as a mixture of the two isomers.…”

“…Based on structure-function analysis (30), the agonist binding pocket of the IP 3 receptor interacts with all three phosphate groups of IP 3 . Screening of derivatives of IP 3 indicates that alterations of the 1-phosphate affects binding affinity to the receptor (31), whereas alterations of the 4,5-diphosphate function affect both affinity (32) and agonist activity (22,33). Thus single-caged IP 3 , which has either exposed 1-and 4-phosphates or exposed 1-and 5-phosphates, might act as a competitive antagonist to the IP 3 receptor.…”

Pretreatment with d-myo-Inositol Trisphosphate Reduces Infarct Size in Rabbit Hearts: Role of Inositol Trisphosphate Receptors and Gap Junctions in Triggering Protection

“…That is, the analog delivered as a slow bolus 25 min before the onset of coronary artery occlusion triggered a 35% reduction of infarct size that was comparable in magnitude to that obtained with brief preconditioning ischemia (Gysembergh et al, 1999), an observation corroborated by the 40% reduction of infarct size seen with D-myo-IP 3 in protocols 1 and 2. However, this finding is intriguing given that D-myo-IP 3 is well recognized to be membrane-impermeable and that IP 3 receptors are historically considered to be intracellular (Wilcox et al, 1998;Gysembergh et al, 1999).…”

“…Previous studies from our group have shown that prophylactic administration of D-myo-IP 3 hexasodium, the sodium salt of IP 3 , renders the heart resistant to a subsequent sustained ischemic insult and triggers a reduction of infarct size that is comparable in magnitude to the cardioprotection achieved with ischemic preconditioning (Gysembergh et al, 1999). However, this observation is enigmatic; i.e., whereas IP 3 (and presumably D-myo-IP 3 ) signaling is conventionally initiated by receptor binding, IP 3 receptors have historically been considered to be intracellular (specifically located on the endoplasmic reticulum or in the perinuclear region), and D-myo-IP 3 is well known to be membrane-impermeable (Berridge, 1993(Berridge, , 2002Taylor and Broad, 1998;Wilcox et al, 1998;Gysembergh et al, 1999;Ibarra et al, 2004;Vermassen et al, 2004).One potential explanation for this apparent paradox is that reduction of infarct size triggered by exogenous D-myo-IP 3 is a nonspecific effect that occurs independently of IP 3 receptor binding. In this regard, there is one report of an apparent increase in the fluidity of in vitro liposomal membrane preparations with D-myo-IP 3 (Brailoiu et al, 1998), the physiologic relevance and mechanisms of which are unknown.…”

“…sidered to be intracellular (specifically located on the endoplasmic reticulum or in the perinuclear region), and D-myo-IP 3 is well known to be membrane-impermeable (Berridge, 1993(Berridge, , 2002Taylor and Broad, 1998;Wilcox et al, 1998;Gysembergh et al, 1999;Ibarra et al, 2004;Vermassen et al, 2004).…”