Signal transduction is the process whereby information from outside the cell is conveyed into the cell. This often involves messenger systems. One such system involves a first messenger, such as a hormone, which binds to a cell surface receptor. The binding stimulates production of a second messenger inside the cell. Several molecules have been implicated as second messengers. A widely use one is cyclic AMP (cAMP). cAMP-dependent signal transduction mechanisms involve three separate proteins:

1. A hormone receptor;

2. Adenylate cyclase; and

3. A G protein (Figure 23.12)

G proteins are named based on their ability to bind guanine nucleotides. G proteins are membrane proteins that in the inactive state bind guanosine diphosphate (GDP). G proteins are required for activation of adenylate cyclase by -adrenergic agonists via interactions with receptor systems that activate or inhibit adenylate cyclase. Of the several known G proteins the two best characterized are Gs, a family of G proteins involved in stimulation of adenylate cyclase, and Gi, a closely related family involved in responses that inhibit adenylate cyclase. Both types of G proteins interact with other receptors as well and with target proteins other than adenylate cyclase.

In summary, the signal transduction pathway involves the following steps:

1. Binding of extracellular hormone or agonist to a receptor, typically a -adrenergic receptor - causes a conformational change in the receptor that stimulates it to interact with a nearby molecule of Gs.

2. This in turn stimulates an exchange of bound GDP for GTP--that is, the dissociation of GDP from Gs, to be replaced by GTP (see here). A class of protein factors called guanine nucleotide exchange factors (GEF) assists in the exchange of GDP and GTP.

3. Gs is thereby converted to a protein that activates adenylate cyclase, producing cyclic AMP from ATP.

4. This results in activation of cAMP-dependent protein kinase (protein kinase A), with consequent phosphorylation of target proteins, such as phosphorylase b kinase in cells that activate glycogen phosphorolysis.

5. Phosphorylation of target enzymes results in stimulation or inhibition of metabolic reactions.

Continued activation of Gs depends on the presence of bound GTP.

The hormonal response is limited, and hence is controlled by the presence of a slow GTPase activity on the G protein. Thus, bound GTP is slowly cleaved to GDP, with concomitant loss of the ability to stimulate adenylate cyclase. This process is assisted by a GTPase-activating protein (GAP).

The Gi protein functions similarly, but it responds to extracellular signals whose response is the inhibition of adenylate cyclase, typically 2 agonists. Here the binding of GTP provokes an inhibitory interaction of Gi with adenylate cyclase, which decreases the synthesis of cAMP.

1. G Protein Receptor Coupled Database

2. G Protein Coupled Receptors Point Mutation Database