Inositol 1,4,5-trisphosphate isozymes

Inositol trisphosphate, a water-soluble compound, diffuses from the plasma membrane to the endoplasmic reticulum, where it binds to specific IP3 receptors and causes Ca2+ channels within the ER to open. Sequestered Ca2+ is thus released into the cytosol (step (5)), and the cytosolic [Ca2+] rises sharply to about 10 6 m. One effect of elevated [Ca2+] is the activation of protein kinase C (PKC). Diacylglycerol cooperates with Ca2+ in activating PKC, thus also acting as a second messenger (step (6)). PKC phosphorylates Ser or Thr residues of specific target proteins, changing their catalytic activities (step (7)). There are a number of isozymes of PKC, each with a characteristic tissue distribution, target protein specificity, and role. 

The phospholipases (PLC) isozymes cleave the phosphodiester bond in phos-phatidyl-inositol-4,5-bisphosphate (PIP2) releasing two second messenger molecules inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) as shown before. The /1-isozyme are controlled by the Ga or G y subunits of the heterotrimeric G-proteins coupled to surface receptors. The y-isozymes are substrates for tyrosine kinases, such as growth factors. 

A third mode of entry of Ca2+ into the cells is mediated by the coupling of the receptor to G proteins. It is believed that this is the pathway used by chemokines. The On reaction begins when the agonist induces a conformational change in the receptor which is transmitted to the G protein. The heterodimeric G protein dissociates into Ga and G 3y subunits, both of which can activate different phospholipase C (PLC) isozymes. This enzyme is able to catalyze the hydrolysis of the lipid precursor phosphatidylinositol 4,5-bisphosphate to give both 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). The latter then binds to the IP3 receptor which mobilizes both stored Ca2+ and promotes an influx of external Ca2+. 

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