- Rodger A Liddle, MD
Rodger A Liddle, MD
- Professor of Medicine
- Duke University Medical School
The field of endocrinology and the study of "hormones" began at the turn of the 20th century when Bayliss and Starling described a chemical substance in intestinal extracts that, when injected intravenously, stimulated pancreatic secretion . They named this substance secretin because it caused the pancreas to secrete fluid when acid was present in the gut. This discovery led to a search for other chemical substances that when released from one tissue could excite or stimulate organ function in a different location. The Greek word "hormone," meaning "arise to activity," was used to designate these chemical messengers. It is now known that secretin stimulates pancreatic fluid and bicarbonate secretion leading to neutralization of acidic chyme in the intestine. Secretin also inhibits gastric acid release and intestinal motility.
Despite knowledge of physiological activity, it took more than 50 years for the chemical nature of the hormone secretin to be identified. The amino acid sequence was not determined until the 1960s . Human secretin is a 27 amino-acid peptide, with a molecular weight of 3055 D. Its sequence is conserved across many mammalian species (figure 1).
Similar to other gastrointestinal peptides, secretin is amidated at the C-terminus. It is the founding member of the secretin/glucagon/vasoactive intestinal polypeptide family of gastrointestinal hormones. The gene structure of preprosecretin contains an N-terminal signal peptide, a short peptide sequence, secretin, and a C-terminal extension peptide . The gene encoding secretin is selectively expressed in specialized enteroendocrine cells of the small intestine, called S cells. The details of secretin gene transcriptional control have been studied in secretin-producing islet cells .
Immunocytochemistry has demonstrated that secretin-producing cells are found along the small intestine (figure 2) . Other sites shown to produce secretin mRNA include the hypothalamus, cortex, cerebellum, and brainstem [3,6].
The secretin receptor is a member of the family of G protein-coupled receptors (GPCRs), within which the secretin/glucagon family is structurally unique. This group consists of receptors for secretin, glucagon, calcitonin, parathyroid hormone, pituitary adenylyl cyclase-activating peptide (PACAP), vasoactive intestinal polypeptide, and others. These receptors lack structural signature sequences present in the rhodopsin/beta-adrenergic receptor family (such as a DRY motif — Asp-Arg-Tyr — at the end of the third transmembrane spanning domain), which appear to be important in receptor coupling to G proteins. Secretin binds to its specific heptahelical membrane receptor and activates the heterotrimeric G protein, Gs, leading to elevation of cellular cAMP levels. This second messenger begins the signaling cascade that initiates appropriate cell physiological responses. (See "Peptide hormone signal transduction and regulation".)
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