A series of inositol 1,4,5-trisphosphate (IP 3 ) analogs and positional isomers was examined to explore the structure-activity relationships among IP 3 5-phosphatase, IP 3 3-kinase, and the release of Ca 2+ . All analogs with additional groups on the 2nd position of IP 3 inhibited the hydrolysis of [5- 32 P]IP 2 catalyzed by erythrocyte ghosts, with a lower K(i) value than seen with IP 3 . IP 3 dehydroxylated at the 2nd position also had a lower K(i), while 2,4,5-IP 3 or cyclic (1:2),4,5-IP 3 had higher K(i) values. Among these compounds 2-deoxy-IP 3 was as potent as IP 3 in inhibiting the phosphorylation by [ 3 H] IP 3 -3-kinase in rat brain cytosol. The other compounds, except for 2,4,5-IP 3 inhibited the phosphorylation, however, 2-30 times higher concentrations were required. By lowering free Ca 2+ , the concentrations required for half-maximal inhibition were low, while those of IP 3 , 2-deoxy-IP 3 , and positional isomers remained unchanged. These compounds acted as full agonists in releasing Ca 2+ from permeabilized macrophages, although 1.6-50-fold higher concentrations than IP 3 were required. These compounds also inhibited the binding of [ 3 H]IP 3 to rat cerebellum and bovine adrenal cortex microsomes, but the potencies were 2.9-33 times less than that of IP 3 . Thus, the 2nd position of IP 3 can be modified with only a slight loss of biological activity.
|Number of pages||6|
|Journal||Journal of Biological Chemistry|
|Publication status||Published - Dec 20 1989|
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology