Second messengers receptor tyrosine kinases

G proteins get their name because they bind GTP as part of their effect An example is the G protein that is linked to the epinephrine receptor and leads to the production of cAMP as a second messenger. Receptor tyrosine kinases have a different mode of action. When they bind their hormone, they phos-phorylate tyrosine residues on themselves and other target proteins, which then act as a second messenger. Insulin is an example of a hormone that binds to a receptor tyrosine kinase. 

Cytokines are small proteins synthesized de novo. They mediate and regulate functions such as immunity and inflammation. Cytokines bind to specific membrane receptors, signaling the cell via second messengers (often tyrosine kinases) to alter gene expression. Ty pical effects of cytokines include altered expression of membrane proteins (including cytokine receptors), proliferation, and secretion of effector molecules. 

Multiple interactions are also being demonstrated between the traditional second-messenger pathways and the MAPK cascades. Free (3y G protein subunits, generated upon activation of receptors coupled to the G family, lead to activation of the ERK pathway. The mechanism by which this occurs, which may involve an interaction between the subunits and Ras or Raf, is a subject of intensive research (see Ch. 19). In addition, increases in cellular Ca2+ concentrations lead to stimulation of the ERK pathway, apparently via phosphorylation by CaMKs of proteins, for example She and Grb, that link growth factor receptor tyrosine kinases to Ras. Activation of the... 

Activation of receptor tyrosine kinases leads to stimulation of phospholipid metabolism and to the generation of multiple second messengers. Phospholipase Cy binds through its SH2 domain to phosphotyrosine sites on the receptor molecules and is thereby activated. As a consequence of phospholipase Cy activation, Ca2+ and diacyl-glycerol signals are produced leading, e. g., to the activation of protein kinase C isoenzymes and of CaM kinases. 

Receptor Tyrosine Kinase-coupled Second Messengers... 

Another important type of second-messenger system involves a receptor type called a receptor tyrosine kinase. These receptors span the membrane of the cell and have a hormone receptor on the outside and a tyrosine kinase portion on the inside. There are several subclasses of these receptor kinases, as shown in Figure 24.13. The best known of these is class 11, which includes the insulin receptor (which we will look at in more detail in Secrion 24.5). 

Receptor tyrosine kinases are a third important type of membrane protein involved in second-messenger systems. 

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. 

Some water-soluble hormones bind to receptors with intrinsic protein kinase activity (often tyrosine kinases). In this case, no second messenger is required for protein kinase activation. The insulin receptor is an example of a tyrosine kinase receptor. 

Insulin binding activates the tyrosine kinase activity associated with the cytoplasmic domain of its receptor as shown in F jure 1-9-4. There is no trimeric G protein, enzyme, or second messenger required to activate this protein tyrosine kinase activity ... 

There are several mechanisms whereby antidepressants can modify intracellular events that occur proximal to the posts)maptic receptor sites. Most attention has been paid to the actions of antidepressants on those pathways that are controlled by receptor-coupled second messengers (such as cyclic AMP, inositol triphosphate, nitric oxide and calcium binding). However, it is also possible that chronic antidepressant treatment may affect those pathways that involve receptor interactions with protein tyrosine kinases, by increasing specific growth factor synthesis or by regulating the activity of proinflammatory cytokines. These pathways are particularly important because they control many aspects of neuronal function that ultimately underlie the ability of the brain to adapt and respond to pharmacological and environmental stimuli. One mechanism whereby antidepressants could increase the s)mthesis of trophic factors is... 

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