Medical Physiology, 3rd Edition

Pepsinogen Secretion

Chief cells, triggered by both cAMP and Ca2+ pathways, secrete multiple pepsinogens that initiate protein digestion

The chief cells in gastric glands, as well as mucous cells, secrete pepsinogens, a group of proteolytic proenyzmes (i.e., zymogens or inactive enzyme precursors) that belong to the general class of aspartic proteinases. They are activated to pepsins by cleavage of an N-terminal peptide. Pepsins are endopeptidases that initiate the hydrolysis of ingested protein in the stomach. Although eight pepsinogen isoforms were initially identified on electrophoresis, recent classifications are based on immunological identity, so pepsinogens are most often classified as group I pepsinogens, group II pepsinogens, and cathepsin E. Group I pepsinogens predominate. They are secreted from chief cells located at the base of glands in the corpus of the stomach. Group II pepsinogens are also secreted from chief cells but, in addition, are secreted from mucous neck cells in the cardiac, corpus, and antral regions.

Pepsinogen secretion in the basal state is ~20% of its maximal secretion after stimulation. Although pepsinogen secretion generally parallels the secretion of acid, the ratio of maximal to basal pepsinogen secretion is considerably less than that for acid secretion. Moreover, the cellular mechanism of pepsinogen release is quite distinct from that of H+ secretion by parietal cells. Release of pepsinogen across the apical membrane is the result of a novel process called compound exocytosis, in which secretory granules fuse with both the plasma membrane and other secretory granules. This process permits rapid and sustained secretion of pepsinogen. After stimulation, the initial peak in pepsinogen secretion is followed by a persistent lower rate of secretion. This pattern of secretion has been interpreted as reflecting an initial secretion of preformed pepsinogen, followed by the secretion of newly synthesized pepsinogen. However, more recent in vitro studies suggested that a feedback mechanism may account for the subsequent reduced rate of pepsinogen secretion.

Two groups of agonists stimulate chief cells to secrete pepsinogen. One group acts through adenylyl cyclase and cAMP, and the other acts through increases in [Ca2+]i.

Agonists Acting via cAMP

Chief cells have receptors for secretin/VIP, β2 adrenergic receptors, and EP2 receptors for PGE2 (see p. 64). All these receptors activate adenylyl cyclase. At lower concentrations than those required to stimulate pepsinogen secretion, PGE2 can also inhibit pepsinogen secretion, probably by binding to another receptor subtype.

Agonists Acting via Ca2+

Chief cells also have M3 muscarinic receptors for ACh, as well as receptors for the gastrin/CCK family of peptides. Unlike gastric acid secretion, which is stimulated by the CCK2 receptor, pepsinogen secretion is stimulated by the CCK1 receptor, which has a much higher affinity for CCK than for gastrin. Activation of both the M3 and CCK1 receptors causes Ca2+ release from intracellular stores by IP3 and thereby raises [Ca2+]i. However, uncertainty exists about whether increased Ca2+ influx is also required and about whether PKC also has a role.

Of the agonists just listed, the most important for pepsinogen secretion is ACh released in response to vagal stimulation. ACh not only stimulates chief cells to release pepsinogen, but also stimulates parietal cells to secrete acid. This gastric acid produces additional pepsinogen secretion by two different mechanisms. First, in the stomach, a fall in pH elicits a local cholinergic reflex that results in further stimulation of chief cells to release pepsinogen. Thus, the ACh that stimulates chief cells can come both from the vagus and from the local reflex. Second, in the duodenum, acid triggers the release of secretin from S cells. By an endocrine effect, this secretin stimulates the chief cells to release more pepsinogen. The exact role or roles of histamine and gastrin in pepsinogen secretion are unclear.

Low pH is required for both pepsinogen activation and pepsin activity

Pepsinogen is inactive and requires activation to a protease, pepsin, to initiate protein digestion. This activation occurs by spontaneous cleavage of a small N-terminal peptide fragment (the activation peptide), but only at a pH that is <5.0 (Fig. 42-12). Between pH 5.0 and 3.0, spontaneous activation of pepsinogen is slow, but it is extremely rapid at a pH that is <3.0. In addition, pepsinogen is also autoactivated; that is, newly formed pepsin itself cleaves pepsinogen to pepsin.

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FIGURE 42-12 Activation of the pepsinogens to pepsins. At pH values from 5 to 3, pepsinogens spontaneously activate to pepsins by the removal of an N-terminal “activation peptide.” This spontaneous activation is even faster at pH values that are <3. The newly formed pepsins themselves—which are active only at pH values <3.5—also can catalyze the activation of pepsinogens.

Once pepsin is formed, its activity is also pH dependent. It has optimal activity at a pH between 1.8 and 3.5; the precise optimal pH depends on the specific pepsin, type and concentration of substrate, and osmolality of the solution. pH values >3.5 reversibly inactivate pepsin, and pH values >7.2 irreversibly inactivate the enzyme. These considerations are sometimes useful for establishing optimal antisecretory therapy in peptic ulcer disease.

Pepsin is an endopeptidase that initiates the process of protein digestion in the stomach. Pepsin action results in the release of small peptides and amino acids (peptones) that, as noted above, stimulate the release of gastrin from antral G cells; these peptones also stimulate CCK release from duodenal I cells. As previously mentioned, the peptones generated by pepsin stimulate the very acid secretion required for pepsin activation and action. Thus, the peptides that pepsin releases are important in initiating a coordinated response to a meal. However, most protein entering the duodenum remains as large peptides, and nitrogen balance is not impaired after total gastrectomy.

Digestive products of both carbohydrates and lipids are also found in the stomach, although secretion of their respective digestive enzymes either does not occur or is not a major function of gastric epithelial cells. Carbohydrate digestion is initiated in the mouth by salivary amylase. However, after this enzyme is swallowed, the stomach becomes a more important site for starch hydrolysis than the mouth. The stomach itself does not secrete enzymes that hydrolyze starch or other saccharides. Lipid digestion also is initiated in the mouth by lingual lipase. However, significant lipid digestion occurs in the stomach as a result of both the lingual lipase that is swallowed and gastric lipase, both of which have an acid pH optimum (see pp. 927–928).