Inositol trisphosphate metabolism

Estevez F, Pulford D, Stark MJ, Carter AN, Downes CP. Inositol 39. trisphosphate metabolism in Saccharomyces cerevisiae identification, purification and properties of inositol 1,4,5-trisphosphate 40. 6-kinase. Biochem. J. 1994 302 709-716. 

It is now generally accepted that both of the products of phosphatidylinositol 4,5-bisphosphate hydrolysis can function as intracellular second messengers. 1,2-Diacylglycerol can affect a variety of intracellular processes by activation of protein kinase C [ 148, 229, 230]. Inositol 1,4,5-trisphosphate, on the other hand, has been shown to release calcium ions from non-mitochondrial stores in a number of peripheral tissues and may thus be the link between the receptor and the intracellular calcium store in many pharmacological responses [231-233]. Furthermore, it remains a possibility that inositol phospholipid hydrolysis may also have a r61e in calcium gating [221,234]. If inositol phospholipid metabolism is closely coupled to receptor-mediated calcium mobilization, then this response may be a more general consequence of H,-receptor stimulation than other H,-responses. 

We will examine the mechanisms and metabolic effects of hormones. Hormones can either work at the membrane or enter the cell for their functions. Three mechanisms are primary for hormones acting at the membrane, which require a transduction of the message into the cell. These transductions include (1) formation of cAMP, (2) formation of inositol trisphosphate and diacylglycerol, and (3) direct covalent modifications. The hormones that enter the cell have their effects in the nucleus. To show the physiological effects of the hormones and review the integration of carbohydrate and lipid metabolism, these hormones are examined in detail. The effects we examine include not only metabolism and its control, but the roles of individual tissues. 

Alternative second-messenger pathways may be at work in olfactory transduction. The role of cAMP in olfactory transduction is well established. Are there alternative pathways, such as those involving phospholipids and Ca2+ Several groups have reported that certain odorants can elicit an increase in the phosphoinositde second messenger inositol 1,4,5,-trisphosphate (IP3) (Ch. 20). However, there is no clear evidence that IP3 directly mediates an electrical response in OSNs, nor is there a clear rationale for two parallel excitatory odor transduction cascades. However, more recent data support the idea that phos-phoinositides or enzymes related to their metabolism may play a modulatory role, shaping the OSN output by... 

A selection of other tumor suppressor genes is summarized in Table 14.2. Interestingly, an enzyme of phosphatidyl-inositol metabolism has been also identified as a tumor suppressor. The PTEN tumor suppressor gene codes for a phospholipid phosphatase which specifically cleaves a phosphate from the second messenger phosphatidyl-inosi-tol-3,4,5-trisphosphate (PtdInsPj, see 6.6.2). and thus inactivates the messenger (review Maehama and Dixon, 1999). ... 

Fig. 3. The interrelated changes in the metabolism of phosphatidylinositol 4,5-bisphosphate (PIP2) and Ca2+ during activation of the cell by a typical Ca2+-dependent hormone. R, receptor G, guanine regulatory protein PLC, phospholipase C DG, diacylglycerol CK, protein kinase C [Ca2+]sm, the Ca2+ concentration in a cellular domain just beneath the plasma membrane (striped area) Insl,4,SP3, inositol 1,4,5-trisphosphate Insl,3,4,5P4, inositol 1,3,4,5-tetrakisphosphate [Ca2+]c, cytosolic Ca2+ concentration CaM, calmodulin arrows (=>), fluxes of Ca2+ across membranes s=>, energy-dependent fluxes CaY, a calcium pool in specialized compartment of the endoplasmic reticulum. See text for discussion.

Strict adherence to the lowest-locant rule sometimes obscures straightforward metabolic relationships. For example, consider the dephosphorylation of (22) - (23) (Figure 5). The IUPAC (1976) rules require that compound (22) be labeled lD-myo-inositol-l,3,4,5-tetrakisphosphate rather than lL-myo-inositol-l,3,5,6-tetrakisphosphate, so that substituents are attached to carbons with lower numbers, whereas (23) should be labeled lL-myo-inositol-1,5,6-trisphosphate rather than lD-myo-inositol-3,4,5-trisphos-phate. Thus, to describe the dephosphorylation reaction (Figure 5), the necessity to switch between D and L numbering leads to the following statement ... 

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