G Proteins and Signal Transduction

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 G s, a family of G proteins involved in stimulation of adenylate cyclase, and G i, 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 G s.

> 2. This in turn stimulates an exchange of bound GDP for GTP--that is, the dissociation of GDP from G s, 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. G s 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 G s 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 G i 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 G i with adenylate cyclase, which decreases the synthesis of cAMP.

See also: G Protein Families and Subunits, Signal Transduction Agonists and Antagonists, G proteins in vision, Figure 12.13, Metabolic Control Mechanisms (from Chapter 12)

INTERNET LINKS:

> 1. G Protein Receptor Coupled Database

> 2. G Protein Coupled Receptors Point Mutation Database