Signal transduction epinephrine

Many different receptor types are coupled to G proteins, including receptors for norepinephrine and epinephrine (a- and p-adrenoceptors), 5-hydroxytrypta-mine (serotonin or 5-HT receptors), and muscarinic acetylcholine receptors. Figure 2.1 presents the structure of one of these, the uz-adrenoceptor from the human kidney. All members of this family of G protein-coupled receptors are characterized by having seven membrane-enclosed domains plus extracellular and intracellular loops. The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portions of the receptor. The general term for any chain of events initiated by receptor activation is signal transduction. 

Kondo A, Mogi M, Koshihara Y, Togari A. 2001. Signal transduction system for interleukin-6 and interleukin-11 synthesis stimulated by epinephrine in human... 

Extracellular epinephrine (adrenaline) (from the adrenal medulla) activates /33-adrenergic receptors on fat cells to induce the breakdown of triacylglycerols to free fatty acids and glycerol. The intracellular enzyme involved in this process, hormone-sensitive lipase, is activated by protein kinase A. What are the key elements of the signal transduction cascade ... 

Studies by Scmtton et. al. and Stormoiken and his associates, have shown compromised functional response to epinephrine in apparently normal individuals (52,53). Weiss et. al. have described secretion defects from patients with bleeding disorders (54). White et. al. have followed functional response of platelets of patients with diabetes and Hermasky-Pudlak Syndrome (HPS) whose platelets lack dense bodies. Platelets of patients with HPS exhibit compromised response to the action of agonists (55). Hardisty et. al., and Ware and associates, have provided further evidence for altered signal transduction mechanisms. These and other studies seem to suggest that an impaired intracellular calcium flux may be the chief cause of platelet dysfunction (56-58, discussed in other chapters). 

Many hormones, such as epinephrine (adrenaline), alter the activities of enzymes by stimulating the phosphorylation of the hydroxyl amino acids serine and threonine phosphoserine and phosphothreonine are the most ubiquitous modified amino acids in proteins. Growth factors such as insulin act by triggering the phosphorylation of the hydroxyl group of tyrosine residues to form phosphotyrosine. The phosphoryl groups on these three modified amino acids are readily removed thus they are able to act as reversible switches in regulating cellular processes. The roles of phosphorylation in signal transduction will be discussed extensively in Chapter 14. 

Figure 14.8 Epinephrine signaling pathway. The binding of epinephrine to the p-adrenergic receptor initiates the signal-transduction pathway. The process in each step is indicated in black) to the left of each arrow. Steps that have the potential for signal amplification are indicated to the right in green.

The signal-transduction pathway initiated by epinephrine is summarized in Figure 14.8. 

How is the signal initiated by epinephrine switched off subunits have intrinsic GTPase activity, which is used to hydrolyze bound GTP to GDP and P . This hydrolysis reaction is slow, however, requiring from seconds to minutes. Thus, the GTP form of Gc is able to activate downstream components of the signal-transduction pathway before GTP hydrolysis deactivates the subunit. Tn essence, the bound GTP acts as a built-in clock that spontaneously resets the subunit after a short time period. After GTP hydrolysis and the release of P , the GDP-bound form of G then reassociates with to re-form the inactive heterotrimeric protein (Figure 14.9). 

Our consideration of the signal-transduction cascades initiated by epinephrine and insulin included examples of how components of signal-transduction pathways are poised for action, ready to be activated by minor modifications. For example, G-protein a subunits require only the binding of GTP in exchange for GDP to transmit a signal. This exchange reaction is thermodynamically favorable, but it is quite slow in the absence of an appropriate activated 7TM receptor. Similarly, the tyrosine kinase domains of the dimeric insulin receptor are ready for phosphorylation and activation but require the presence of insulin bound between two a subunits to draw the activation loop of one tyrosine kinase into the active site of a partner tyrosine kinase to initiate this process. 

Protein kinases are central to many signal-transduction pathways. Protein kinases are central to all three signal-transduction pathways described in this chapter. In the epinephrine-initiated pathway, cAMP-dependent protein kinase (PKA) lies at the end of the pathway, transducing information represented by an increase in cAMP concentration into covalent modifications that alter the activity of key metabolic enzymes. In the insulin- and EGF-initiated pathways, the receptors themselves are protein kinases and several additional protein kinases participate downstream in the pathways. Signal amplification due to protein kinase cascades are common features of each of these pathways and many others. Furthermore, protein kinases often phosphorylate multiple substrates, including many not considered herein, and by this means are able to generate a diversity of responses. 

The signal-transduction processes in the liver are more complex than those in muscle. Epinephrine can also elicit glycogen degradation in the liver. However, in addition to binding to the p-adrenergic receptor, it binds to the 7TM a-adrenergic receptor, which then initiates the phosphoinositide... 

See also Epinephrine, Glucagon, Action of Glucagon, G Proteins and Signal Transduction... 

Amino acids and their metabolites participate in signal transduction process - hormonal control and the synaptic transmission of nerve impulses. Some compounds, like epinephrine and histamine (see here) participate in both processes. 

In the PIP2-Ca signal transduction system, the signal is transferred from the epinephrine receptor to membrane-bound phospholipase C by G proteins. Phospholipase C hydrolyzes PIP2 to form diacylglycerol (DAG) and inositol trisphos-phate (IP3). IP3 stimulates the release of Ca from the endoplasmic reticulum. Ca and DAG activate protein kinase C. The amount of calcium bound to one of the calcium-binding proteins, calmodulin, is also increased. 

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