Chapter: Modern Pharmacology with Clinical Applications: Mechanisms of Drug Action

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Second-Messenger Systems

Many receptors are capable of initiating a chain of events involving second messengers.

SECOND-MESSENGER SYSTEMS

Many receptors are capable of initiating a chain of events involving second messengers. Key factors in many of these second-messenger systems are proteins termed G proteins, short for guanine nucleotide– binding proteins. G proteins have the capacity to bind guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP).

G proteins couple the activation of several different receptors to the next step in a chain of events. In a num-ber of instances, the next step involves the enzyme adenylyl cyclase. Many neurotransmitters, hormones, and drugs can either stimulate or inhibit adenylyl cy-clase through their interaction with different receptors; these receptors are coupled to adenylate cyclase through either a stimulatory (GS) or an inhibitory (G1) G protein. During the coupling process, the binding and subsequent hydrolysis of GTP to GDP provides the en-ergy needed to terminate the coupling process.

The activation of adenylyl cyclase enables it to cat-alyze the conversion of adenosine triphosphate (ATP) to 3 5 -cyclic adenosine monophosphate (cAMP), which in turn can activate a number of enzymes known as ki-nases. Each kinase phosphorylates a specific protein or proteins. Such phosphorylation reactions are known to be involved in the opening of some calcium channels as well as in the activation of other enzymes. In this system, the receptor is in the membrane with its binding site on the outer surface. The G protein is totally within the membrane while the adenylyl cyclase is within the mem-brane but projects into the interior of the cell. The cAMP is generated within the cell (see Figure 10.4).

Whether or not a particular agonist has any effect on a particular cell depends initially on the presence or absence of the appropriate receptor. However, the na-ture of the response depends on these factors:

·              Which G protein couples with the receptor

·              Which kinase is activated

·              Which proteins are accessible for the kinase to phosphorylate

The variety of possible responses is further in-creased by the fact that receptor-coupled G proteins can either activate enzymes other than adenylate cy-clase or can directly influence ion channel functions.


Many different receptor types are coupled to G pro-teins, including receptors for norepinephrine and epi-nephrine ( α- and β-adrenoceptors), 5-hydroxytrypta-mine (serotonin or 5-HT receptors), and muscarinic acetylcholine receptors. Figure 2.1 presents the struc-ture of one of these, the α2-adrenoceptor from the hu-man 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 ag-onists occur at the extracellular surface, while the inter-action with G proteins occurs with the intracellular por-tions of the receptor. The general term for any chain of events initiated by receptor activation is signal trans-duction.

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