The Discovery of Cholecystokinin

Overview

Cholecystokinin (CCK) is a family of peptides produced by intestinal I-cells and central nervous system neurons. It was first identified in 1928 by Andrew Conway Ivy and Eric Oldberg at Northwestern University, who were searching for an intestinal factor responsible for gallbladder contraction in response to fat in the duodenum. They extracted an active principle from intestinal mucosa and named it "cholecystokinin" — literally "mover of the bile bladder."

A separate physiological observation — that intestinal extracts also stimulated pancreatic enzyme secretion — led Harper and Raper in 1943 to propose a second intestinal hormone they called "pancreozymin." Decades of confusion followed until Viktor Mutt and Erik Jorpes at the Karolinska Institute demonstrated in the 1960s that cholecystokinin and pancreozymin were in fact the same molecule. The hormone was briefly called cholecystokinin-pancreozymin before the shorter name prevailed.

Today, CCK is known as a peptide family encompassing CCK-8, CCK-33, CCK-58, and other forms derived from a single prepro-CCK precursor. The C-terminal eight amino acids (CCK-8) are sufficient for full biological activity. CCK acts through two receptors, CCK1 (formerly CCK-A) and CCK2 (formerly CCK-B, closely related to the gastrin receptor), with roles in digestion, satiety, anxiety, and pain.

Key People

• Andrew Conway Ivy (1893–1978): Physiologist who led the 1928 CCK discovery.
• Eric Oldberg: Ivy's collaborator on the cholecystokinin work.
• Harper and Raper: Identified pancreozymin in 1943.
• Viktor Mutt (1923–1998) and Erik Jorpes: Karolinska biochemists who purified and sequenced CCK and many other gut peptides.
• Gerard P. Smith and James Gibbs: Demonstrated CCK's satiety effects in the 1970s.

Timeline

• 1928: Ivy and Oldberg describe cholecystokinin.
• 1943: Harper and Raper describe pancreozymin.
• 1966: Mutt and Jorpes purify CCK and show identity with pancreozymin.
• 1968: CCK-33 amino acid sequence is published.
• 1973: Gibbs, Young, and Smith show CCK induces satiety in rats.
• 1990s: CCK1 and CCK2 receptors are cloned.

Background

CCK is a classic example of the "brain-gut axis." In the gut, it coordinates digestive responses to a meal: contraction of the gallbladder, secretion of pancreatic enzymes, relaxation of the sphincter of Oddi, and slowing of gastric emptying. In the brain, it is among the most abundant neuropeptides, with roles in anxiety, panic disorders, reward, and nociception.

The Karolinska group's work on CCK also contributed to the broader emergence of gut-peptide research. Mutt and Jorpes, along with Sami Said, isolated and characterized vasoactive intestinal peptide, secretin, gastrin, and others, laying the groundwork for modern gastrointestinal endocrinology. Their bioassay-driven, tissue-extract approach has been largely replaced by molecular techniques but remains a model of systematic peptide discovery.

Modern Relevance

CCK remains an essential concept in digestive physiology. It is used clinically as a provocative test agent for gallbladder function and pancreatic enzyme secretion. CCK1 receptor antagonists have been investigated for irritable bowel syndrome and pancreatitis. CCK2 receptor-targeted imaging agents are explored for tumors expressing CCK2, including medullary thyroid carcinoma.

CCK's role in satiety has inspired therapeutic interest in obesity, though full-length CCK agonists have not reached routine clinical use, largely because of receptor desensitization and tachyphylaxis. CCK also interacts with leptin, GLP-1, PYY, and ghrelin in the complex regulation of appetite, a topic central to modern metabolic research.

Related Compounds

• CCK
• CCK-8
• Gastrin
• Secretin
• PYY