eTopic 25.1 Normal G-Factor Control of Adenylate Cyclase

Cholera toxin, enterotoxigenic E. coli labile toxin, and pertussis toxin, all discussed in Chapter 25, function by subverting the normal activity of adenylate cyclase, the enzyme that synthesizes cAMP. The result is fluid accumulation in the intestine (cholera and E. coli) or lung tissues (pertussis) as a result of an electrolyte imbalance initially caused by excess secretion of Clion. A major player in the secretion of Cl is the cystic fibrosis transmembrane conductance regulator (CFTR). Chloride export via CFTR is activated indirectly by cAMP. (CFTR is so named because a genetically based defect in the CFTR transporter/-regulator manifests as the lung disease cystic fibrosis.) Understanding the way cAMP levels are controlled in the normal host will help understanding of how the toxins cause problems.

Human cells have two types of G-factor complexes, called Gs and Gi, that stimulate and inhibit adenylate cyclase, respectively. The G-factor complexes share beta and gamma subunits but have distinct alpha subunits (Gs-alpha and Gi-alpha). The complexes are normally bound to specific membrane hormone receptors (Fig. 1). Stimulation of the hormone receptor allows GTP to bind the associated G-alpha subunit (replacing a bound GDP). Subsequently, the G-alpha-GTP protein leaves the receptor complex and binds adenylate cyclase, either stimulating camp production (if Gs-alpha) or inhibiting it (if Gi-alpha).

Normally, an intrinsic GTPase activity within the G-alpha protein degrades GTP to GDP. G-alpha proteins bound to GDP are inactive and cannot control adenylate cyclase. Thus, inhibitory and stimulatory G factor–associated GTP turnover controls cAMP levels and thus CFTR activity in normal cells.

In the disease state (text Fig. 25.20, step 5), Gs-alpha protein is ADP-ribosylated by cholera and labile toxin. Modified Gs-alpha protein can still activate adenylate cyclase, but it has a defective GTPase. Because the altered G factor cannot degrade GTP, the protein continually stimulates cAMP production, increasing the levels of cAMP tremendously. In the case of pertussis toxin, ADP-ribosylation of the inhibitory G-factor prevents that protein from dampening adenylate cyclase. Once again, cAMP levels rise. In either case, elevated levels of cAMP stimulate a host enzyme called protein kinase A that activates various ion transport channels (text Fig. 25.20, step 6). One of these channels is the cystic fibrosis transmembrane conductance regulator that controls chloride transport (discussed in text Section 24.4). The resulting electrolyte imbalance causes water to leave cells and accumulate in the surrounding area.


Figure 1  Normal regulation of human cell adenylate cyclase.  Human cells have two G-factor complexes, Gs and Gi, that stimulate and inhibit adenylate cyclase, respectively.