Cholecystokinin and the hormone concept

Abstract

The birth certificate for endocrinology was Bayliss' and Starling's demonstration in 1902 that regulation of bodily functions is not only neuronal but also due to blood-borne messengers. Starling named these messengers hormones. Since then transport via blood has defined hormones. This definition, however, may be too narrow. Thus, today we know that several peptide hormones are not only produced and released to blood from endocrine cells but also released from neurons, myocytes, immune cells, endothelial cells, spermatogenic cells, fat cells, etc. And they are often secreted in cell-specific molecular forms with more or less different spectra of activity. The present review depicts this development with the story about cholecystokinin which was discovered in 1928 as a hormone and still in 1976 was conceived as a single blood-borne peptide. Today's multifaceted picture of cholecystokinin suggests that time may be ripe for expansion of the hormone concept to all messenger molecules, which activate their target cells - irrespective of their road to the target (endocrine, neurocrine, neuronal, paracrine, autocrine, etc.) and irrespective of their kind of activity as classical hormone, growth factor, neurotransmitter, adipokine, cytokine, myokine, or fertility factor.

Keywords: bioactive peptides; cholecystokinin; growth factors; hormone concept; neurotransmitter peptides.

Figure 1

The amino sequence of porcine cholecystokinin-33 (CCK-33), the originally identified CCK-peptide (Mutt & Jorpes (39)). The bioactive CCK-8 sequence (26, 27, 28, 29, 30, 31, 32, 33) is underlined. Only the amino acids in the encircled positions no. 7, 9, 10, and 15 differ from those in the human sequence (Met, Ile, Val, and Asn, respectively).

Figure 2

The bioactive sequences of peptide systems belonging to the cholecystokinin (CCK) family. CCK and the antral hormone, gastrin (43, 44), are the only mammalian members of the family. Caerulein and phyllocaerulein are identified from frog skin extracts (45, 46). Cionin is a neuropeptide isolated from the central ganglion of the protochord, ciona intestinalis (47). Note the unique disulfated sequence, which might suggest that cionin may resemble a common ancestor of CCK and gastrin (48). The core of the bioactive sequences, the common C-terminal tetrapeptide amide, is boxed. The lower panel shows the bioactive sequences of the insect neuropeptides, the sulfakinins, which are homologous to vertebrate and protochordian members of the CCK family (49, 50). Also their C-terminal tetrapeptide amide sequence is boxed.

Figure 3

The posttranslational maturation of preprocholecystokinin in the endocrine I-cells of the small intestine. Mono-and dibasic cleavage sites (arginyl (R) and lysyl (K) residues) are indicated on the schematic figure of preprocholecystokinin (upper part of the figure). In the remaining part of the figure, the asterisks (*) indicate tyrosyl O-sulfation sites on the procholecystokinin processing intermediates and bioactive endproducts. Decisive processing enzymes (sulfortransferases, prohormone convertases, carboxypeptidase E, and the amidation enzyme (pepdityl-glycyl-α-amidating monooxygenase complex (PAM)) are also mentioned at the cellular level of the posttranslational processing pathway, where they act. In the intestinal endocrine I-cells, prohormone convertase 1/3 (PC 1/3) is predominant, whereas prohormone convertase 2 (PC 2) predominates in cerebral CCK neurons (see also 62). CCK-83 has been identified in tissue extracts but not in plasma (63).

Figure 4

The concentrations of bioactive CCK in plasma vs gallbladder emptying during a mixed meal in normal human subjects. Data from (141) with permission.