General

Cholecystokinin (CCK) and gastrin are peptides with important roles in gastrointestinal and neural physiology. CCK was discovered in 1928 by Ivy and Oldberg [14] as a factor released by the small intestine in response to fat ingestion that resulted in gallbladder contraction. Later, Harper and Raper [12] discovered a factor that stimulated pancreatic enzyme secretion, and it was ultimately the work of Mutt and Jorpes at the Karolinska Institutet that demonstrated that both of these activities were present in a single peptide, the 33-amino acid form of CCK [18]. Gastrin was initially described in 1905 by Edkins [10]. When this was isolated and sequenced by Gregory and Tracy [11], it became clear that both hormones shared their carboxyl-terminal heptapeptide amide, an important region for their biological activity. It is of note that the "gastrin-like" activity originally identified in the central nervous system was subsequently identified to be CCK [22], one of the most abundant human brain peptides.

Both CCK and gastrin are linear peptides that occur in a series of molecular forms having different lengths that share their carboxyl-terminal pharmacophoric domains. CCK comes from a 115 amino acid precursor (preproCCK) [6] to yield forms 58, 39, 33, 22, and 8 amino acids in length, all containing a sulfated tyrosine residue seven residues from their carboxyl terminus and all containing a carboxyl-terminal amide. Gastrin, in contrast, comes from a 101-amino acid preprohormone and is processed to yield 34 and 17 amino acid length forms, with each present as sulfated and unsulfated forms, with the tyrosine six residues from their carboxyl terminus being variably sulfated [1]. All gastrins are normally amidated [4].

All of the physiological roles for CCK relate to nutritional homeostasis, with activities to stimulate gallbladder contraction, pancreatic exocrine secretion, gastric emptying, intestinal transit, and satiety [3]. The major physiological role for gastrin is the stimulation of gastric acid secretion [8]. Both hormones have other actions that have been described in pathological states, such as their trophic effects on epithelial targets and cancers [13].

CCK receptor heterogeneity and localisation

There are single and distinct genes that encode for CCK and gastrin receptors [5,15,20-21]. These are now called CCK₁ and CCK₂ receptors, respectively. They were previously classified as Type A (alimentary) and B (brain), respectively, based on their prominent locations. Both genes are organized similarly, with similar numbers of exons and with analogous exon-intron boundaries. Variable pre-mRNA splicing can yield distinct spliceoforms [7,16]. This can occur in different regions of the brain, in different individuals, and in normal versus neoplastic tissues.

Consistent with the actions described above, CCK₁ receptors have been localized to gallbladder muscularis, pancreatic nerves, nerves and muscle along the gastrointestinal tract, and in several discrete areas of the brain [19]. These include the nucleus solitarius, the interpeduncular nucleus, and the nucleus accumbens, as well as the area postrema, the dorsal raphe, the substantia nigra, and the ventral tegmentum. CCK₂ receptors have been localized to acid secreting cells in the the oxyntic mucosa of the stomach and extensively throughout the brain [19]. Gastric and central nervous system CCK₂ receptors have been shown to represent the same molecule, encoded by a single gene [15].

CCK receptor ligands

Distinct structure-activity relationships exist for CCK₁ and CCK₂ receptor activation by natural peptide ligands. The structural selectivity of the CCK₁ receptor is more discriminating, requiring the carboxyl-terminal heptapeptide amide of all forms of CCK [9]. This includes the sulfated tyrosine residue. Therefore, this receptor binds CCK with high affinity and CCK is highly potent to stimulate it, whereas gastrin peptides bind with low affinity and are weak agonists. For the CCK₂ receptor, the minimally active fragment is the carboxyl-terminal tetrapeptide amide that is shared by all gastrin and CCK peptides [17]. It is of interest, therefore, that all of these hormonal peptides have similar affinities and potencies to stimulate the CCK₂ receptor.

Many non-peptidyl ligands have been developed for CCK₁ and CCK₂ receptors [2]. Most of these represent antagonists. The potential therapeutic areas being considered for these agents include anxiety, nociception, appetite control, depression, learning, memory, neuroprotection, drug dependence, and gastrointestinal dysmotility states. None of these agents are currently approved for standard clinical use.

Signal transduction

Both types of CCK receptors are Family A guanine nucleotide-binding protein (G protein)-coupled receptors with seven transmembrane segments and characteristic signatures for this group of receptors. They are closely structurally related and signal similarly, through the Gq group of hetertrimeric guanine nucleotide-binding proteins [23]. Agonist stimulation normally leads to stimulation of phospholipase C and increases in intracellular calcium [23].

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