BS2550 - Intracellular signaling IV: Inositol, phosphoinositide's, and inositol phosphates - 30/11/20 Phosphoinositides and inositol phosphates Phosphoinositides - Membrane bound - inositol head group, which is attached, via phosphate, to glycerol and two fatty acids. - Multiple phosphates on inositol produces different species of chemicals with differing roles Inositol phosphates - Related, but are different. 2-O3PO PIP2 I OH OPO32 OH OH 0 O O R O O P R 2 - Species will have an inositol ring, but it is not attached to any long fatty acid chains (not on membrane as on fatty acid chains can't anchor it) OH 2-O3PO OPO32- IP2 OH - Inositol are cytosolic - be phosphorylated at multiple places. OH OH The structure of myo-inositol - Inositol (cyclohexanehexol) has a 6 carbon ring with 6 OH groups. - Due to the nature of its carbon ring, it has a planar structure, which provides isometric structures. - The positions of the different carbons are very important in helping identify which carbons are phosphorylated. - Inositol includes a group of stereoisomers, and so inositol and myo-inositol are interchangeable Intake and uptake of inositol - Human neuronal levels are 4-5mM, and inositol is a component of diet in low concentrations - Inositol is taken up into tissue via a sodium-dependent inositol co-transporter that also mediates glucose uptake. OH P -OH Inositol phosphates 2 HO. 6 - InsP3 = key inositol phosphate HO- OH - InsP3 (Inositol trisphosphate) is one of four key secondary messengers. 3 15 OH P I(1,4,5)P3 myo-inositol - Myo-inositol initially does not possess any phosphate groups, and the addition of phosphate groups at different positions gives 63 different signaling molecules. P P P - InsP3 is deactivated by phosphorylation, and the inositol head group is recycled by a series of phosphates P P (1,3,4,5)P4 P P P P IP. P P P P P I(1,3,4,5,6)P5 P P P P P P P P P PP-IPS or IP7
The structure and function of InsP3 - Inositol 1,4,5 - trisphosphate has a very specific target effect since moving phosphates to different positions causes inactivation - The phosphate in the 1- position appears to be important in the binding of IP3 to the receptor. - Phosphates in the 4- and 5- positions are involved in the Ca2+ efflux - InsP3 acts to bind specific receptors on the ER to trigger calcium release. InsP3 is produced from PIP2 > a phosphoinositide. - Signal induced activity of phospholipase C (PLC) gives rise to cleavage of PIP2 to produce InsP3, and other phospholipases will cleave at different points. - PLC activation occurs via multiple pathways Bipolar disorder, and the inositol depletion theory - Berridge proposed that medicinal treatments for bipolar disorder acted to deplete the levels of inositol. - A signal will bind to the receptor and that will activate phospholipase C, o will produce IP3, will be broken down to IP2 and IP1, and inositol, o and then all will be recycled back via PIP2. - It is also