Secondmessenger 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 number 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 energy needed to terminate the coupling process.

The activation of adenylyl cyclase enables it to catalyze the conversion of adenosine triphosphate (ATP) to 3'5'-cyclic adenosine monophosphate (cAMP), which in turn can activate a number of enzymes known as kinases. 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 membrane 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 nature 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

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