| Inositol 1,4,5-trisphosphate (IP3)
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| IP3 is important in intracellular calcium mobilization
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The rapid production (<1 second) and removal (t½ = 4 seconds in liver) of IP3 that precedes an increase in intracellular Ca2+ concentration implied that it could be a second messenger signaling calcium mobilization. Two types of experiment confirmed that IP3 is indeed a second messenger:
- microinjection of IP3 into cells, or simply including IP3 in incubations of cells in which detergent treatment had induced the formation of holes or pores in the plasma membrane (permeabilized cells), mobilized calcium in the absence of hormone stimulation;
- structure-function analyses of a variety of inositol phosphate molecules suggested that calcium mobilization was dependent on specific IP3 receptors.
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| IP3 receptors that exhibit IP3 binding and calcium release have now been cloned. These receptors are expressed on the endoplasmic reticulum of all cells as a family of related glycoproteins (molecular mass 250 kDa) comprising six transmembrane-spanning domains. The active receptor is expressed as a multimer of four IP3 receptor molecules; this tetrameric structure gives rise to cooperativity in Ca2+-channel activity. It has been estimated that stimulated IP3 (typically 2-3 mmol/L) releases 20-30 calcium ions. This calculation reveals the amplification inherent in this signaling cascade because, typically, only nanomolar concentrations of growth factor are required to elicit millimolar concentrations of this second messenger. Consistent with the transient nature of the release of intracellular calcium that is observed after hormone receptor ligation, cellular concentrations of IP3 are rapidly returned to resting values (0.1 mmol/L) by more than one route of degradation (Fig. 38.9).
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