The Store as a Source of Activator Calcium

The second messenger linking activation of surfece receptors by spasmogens in smooth muscle to release of intracellular Ca has been identified as IP3. IP3 is formed by activated receptor stimulation of a cell membrane enzyme, PLC, which hydrolyses a lipid constituent of the cell membrane, phosphatidylinositol bisphosphate (PIP2 Fig. 9.4). 

PIP2 is formed in the cell membrane by the successive phosphorylation of the membrane phospholipid phosphatidylinositol (PI) to phosphatidylinositol 4-monophosphate (PIP) and then to PIP2. PIP2 is readily recycled by specific phosphomonoesterases to PIP and eventually back to PI. This cycle continues at rest until stimulation of surface receptors occurs. Receptor 

This pathway is ubiquitous in many cell types and has also been imphcated in the mechanism of phar-macomechanical coupling in ASM. Phosphoinositol metabolism and rapid rises in the cellular levels of IP3 follow stimulation by a variety of a nists - carbachol, histamine, neurokinins and leukotrienes in canine, guinea-pig and bovine ASM (Hashimoto et al., 1985 Grandordy et al., 1986, 1988 Duncan et /, 1987 Kardasz a al., 1988 Chilvers et al., 1989, 1991). This rise in IP3 precedes contraction (Duncan et al., 1987). 

The initial high levels of IP3 in response to agonist-receptor interaction are not maintained during the sustained phase of contraction (Chilvers et al, 1989 Chilvers and Nahorski, 1990). IP3 fells to baseline levels within a minute of the onset of contraction. I(1,4,5)P3 is metabohzed by two pathways, both of which are activated by increases in cytosolic Ca hydrolysis by a 5-phosphatase enzyme to I(1,4)P2, or phosphorylation to I(1,3,4,5)P4 and subsequent hydrolysis to its inactive isomer I(1,3,4)P3 (Chilvers and Nahorski, 1990). No physiological role for I(1,3,4,5)P4 has yet been identified in airway smooth muscle, although in other cells evidence exists that I(1,3,4,5)P4 may modulate plas-malemmal Ca ion channels (Irvine and Moor, 1986). The only phosphoinositide metabolite which has been shown to release stored Ca in ASM is I(1,4,5)P3. 

The IP3 receptor in ASM is competitively blocked by low molecular weight heparin (Chopra etal., 1989). The sensitivity of this effect is high, half maximal inhibition of IP3-induced Ca release occurring at 0.8/tgml low molecular weight heparin. The inhibitory effect is struc-tiually specific to low molecular weight heparin and its 

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