BS2550 - Neuronal and Cellular Signalling Lecture 12 Inositol Phosphoinositides are membrane bound. They have an inositol head group, attached via a phosphate, to a glycerol and two fatty acids. OH 2-03PO OPO-2 OH OH R The multiple phosphates on inositol producing compounds gives differing roles. R Inositol phosphates is cytosolic. Phosphorylated inositol at multiple places. OH There are multiple phosphates on inositol produces compounds with differing roles. Myo-inositol (cyclohexanehexol) is a cyclic poly alcohol. - Does not contain any phosphate groups. - We can add phosphates to any carbons within the ring. The position of hydroxyl groups is important, so they are numbered. It has a structural similarity to glucose. OPO32- OH 2-O3PO 3 OH OH OH OH 2 OH 6 OH 5 HO 4 OH Inositol is a group of compounds (stereoisomers), the major stereoisomer is myo-inositol. Naming rules: - The first part of the name is always inositol. - The second part is the position of the phosphate on the ring. - Then we have a prefix (bis, tris, tetra etc.). - Finally, phosphate. Human neuronal levels of myo-inositol is around 4-5mM. We can get inositol from our diet, but this is at relatively low concentrations. - It is naturally occurring in wheats, pulses, and fruits. Inositol is taken up into tissues via a sodium-dependent inositol co-transporter that also mediates glucose uptake.
One key inositol phosphate (IP3) is an important second messenger. The single key role is to bind to specific receptors on the endoplasmic reticulum to trigger a calcium release. IP3 is deactivates by dephosphorylation. The inositol head group is recycled by a series of phosphatases. The structure of IP3: - Moving phosphates to different positions causes inactivation of the protein. - The phosphate in the 1 position appears to be important in binding IP3 to the receptor. - The phosphate in the 4 and 5 positions are involved with the calcium efflux. Signal induced activity of phospholipase C (PLC) gives rise to the cleavage of PIP2 to produce IP3. Other phospholipases cleave at different points. The dampening down of an over-active pathway involving inositol phosphate recycling remains a leading theory on how treatments for bipolar disorder work. Diacylglycerol is another important second messenger. DAG produced by PLC cleavage of PIP2. This is a membrane bound second messenger. Its primary role is to activate protein kinase C. PKC translocates the membrane to bind DAG. DAG usually contains C1 - a saturated fatty acid, and C2 - an unsaturated fatty acid. The activation of protein kinase C: (B) Pseudosubstrate binding at active site - Activation of PKC is dependent on the elevation of both calcium and DAG. - PKCs are a family of protein kinases located in the inactive form of the cytosol. - An increase in calcium in the cytoplasm leads to the relocation of the enzyme to the plasma membrane where it is activated by DAG. Inactive protein kinase C in solution Activated protein kinase C bound to membrane CIA C2 C1B Diacylglycerol Calcium ion