Inositol Trisphosphate Pathway

The outline of another important second-messenger system was elucidated during the last few years. Chemical messengers that act via this system include a variety of hormones (e.g., catecholamines, vasopressin, and angiotensin) as well as some neurotransmitters (e.g., acetylcholine acting on pancreatic acinar cells to stimulate secretion of digestive 

Meanwhile, the polar IP3 moiety binds to intracellular receptors on the endoplasmic reticulum, resulting in the liberation of calcium into the cytosol. The calcium binds to calmodulin, which then activates another group of protein kinases (the Ca2+/CaM-dependent protein kinases). Hormonal stimulation can be short-lived because IP3 and DG are rapidly degraded to inactive forms that are ultimately recycled to PIP2 Ca2+ is pumped back into the endoplasmic reticulum, where it is sequestered. 

IP3 is rapidly degraded to inactive IP2 and then on to inositol. Meanwhile, diacylglycerol is phosphorylated and then converted to CDP-diacylglycerol, which combines with inositol to form phosphatidylinositol. The latter is subsequently phosphorylated in two steps to PIP2. The degradation and resynthesis of PIP2 completes the so-called phosphatidylinositol cycle. 

Activation of steroid hormone receptors by the hormone. In the absence of the hormone, the steroid receptors are complexed through the hormone-binding domain to another protein known as heat shock protein 90 (hsp90). Both the hormone-binding domain and the hsp90 prevent functional interaction of the receptor with DNA. Binding of the hormone frees the receptor from hsp90 and promotes dimerization of the receptor, which can then bind to the palindromic hormone response element (HRE) and activate transcription. 

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Multicomponent Hormonal Systems Facilitate a Great Variety of Responses The Guanylate Cyclase Pathway Calcium and the Inositol Trisphosphate Pathway Steroid Receptors Modulate the Rate of Transcription... 

Barac Y.D., Zeevi-Levin N., Yaniv G., Reiter L, Mihnan F., Shilkrut M., Coleman R., Abassi Z., Binah O. The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes. Cardiovasc. Res. 68 (2005) 75-86. 

This can be illustrated by known interactions between the cAMP and Ca2+ pathways. A first messenger that initially activates the cAMP pathway would be expected to exert secondary effects on the Ca2+ pathway at many levels via phosphorylation by PKA. First, Ca2+ channels and the inositol trisphosphate (IP3) receptor will be phosphorylated by PKA to modulate intracellular concentrations of Ca2+. Second, phospholipase C (PLC) is a substrate for PKA, and its phosphorylation modulates intracellular calcium concentrations, via the generation of IP3) as well as the activity of PKC, via the generation of DAG, and several types of CAMK. Similarly, the Ca2+ pathway exerts potent effects on the cAMP pathway, for example, by activating or inhibiting the various forms of adenylyl cyclase expressed in mammalian tissues (see Ch. 21). 

Francesconi, A. and Duvoisin, R. (2000) Opposing effects of protein kinase C and protein kinase A on metabotropic glutamate receptor signaling selective desensitization of the inositol trisphosphate/Ca2+ pathway by phosphorylation of the receptor-G protein-coupling domain. Proc. Natl. Acad. Sci. USA 97,6185-6190. 

Figure 11.21 Outline of synthesis of phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine. Note in the synthesis of phosphatidylinositol, the free base, inositol, is used directly. Inositol is produced in the phosphatase reactions that hydrolyse and inactivate the messenger molecule, inositol trisphosphate (IP3). This pathway recycles inositol, so that it is unlikely to be limiting for the formation of phosphatidylinositol bisphosphate (PIP )- This is important since inhibition of recycling is used to treat bipolar disease (mania) (Chapter 12, Figure 12.9). Full details of the pathway are presented in Appendix 11.5. Inositol, along with choline, is classified as a possible vitamin (Table 15.3).

Two pathways from the activated receptor are shown. At the left is activation of phospholipase Cy and formation, at a membrane-bound site, of inositol trisphosphate and diacylglycerol (DAG). The main pathway, in the center, activates Ras with the aid of the G protein Sos. Activated Ras, in turn, activates Raf and successive components of the MAPK cascade. At the right a seven-helix receptor activates both phospholipase C(3 and Ras via interaction with a (3y subunit. (B) A generalized scheme for the MAP kinase pathway. See Seger and Krebs.380... 

After activation of the TCR, there is induction of Src family tyrosine kinase (p56lek), which phosphorylates phospholipase Oyl. This is followed by the hydrolysis of phosphatidylinositol 4,5-bisphosphate, resulting in the production of diacyl-glycerol (DAG) and inositol trisphosphate (IP3). Protein kinase C is activated by DAG, which phosphorylates Ras. Ras is a GTPase and its phosphorylation induces Raf and initiation of MAP kinase signaling pathway. IP3 is involved in calcium-dependent activation of IL-2 gene expression via nuclear factor of activated T cells (NFAT). 

The opposing effects on smooth muscle (A) of a- and p-adrenoceptor activation are due to differences in signal transduction, ai -Receptor stimulation leads to intracellular release of Ca2+ via activation of the inositol trisphosphate (IP3) pathway. In concert with the protein calmodulin, Ca2+ can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin (— vasoconstriction). 012-Adrenoceptors can also elicit a contraction of smooth muscle cells by activating phospholipase C (PLC) via the py-subunits of G, proteins. 

It is fitting to introduce the phospholipase pathways here because they are controlled by small G proteins. Phospholipases C and D (PLC, PLD) are controlled by Rho/Arf and Cdc42 and Src tyrosine kinases participate in the control of PLD. 36 Phospholipases form potent second messengers, such as inositol trisphosphate (IP3) and diacylglycerol (DAG). In Fig. 4.6a the reactions catalysed by phospholipases C and D and the connections between phospholipases C and D are summarized, and in Fig. 4.6b the regulatory pathways that activate phospholipase D synergistically are summarized.37... 

Gq protein-coupled phosphatidylinositol-Ca " " pathway. The binding of a hormone at a specific receptor site results in the activation of G-protein which, in turn, activates phospholipase C via Gga-OTP-protein. The action of phospholipase C on phosphatidylinositol 4,5-bisphosphate (PIP2) yields inositol trisphosphate (IP3) and diacylglycerol (DAG) which, along with phosphatidylserine (PS), activates protein kinase C. IP3 binds to receptors on SER, releasing Ca " which, in turn, activates another set of protein kinases. -I-, Activation. 

The receptors for sweetness and bitterness act via cell-surface receptors linked to intracellular formation second messengers. There is evidence that both cyclic adenosine monophosphate (cAMP) (section 1.3.2) and inositol trisphosphate (section 10.3.3) mechanisms are involved, and more than one signal transduction pathway may be involved in the responses to sweetness or sourness of different compounds. Some compounds may activate more than one type of receptor. 

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