It has been demonstrated that nerve fibers that are not strictly related to the sympathetic, parasympathetic, or sensory nervous system innervate the endocrine pancreas. These nerve fibers have been shown to harbor different neurotransmitters from the other types of autonomic nerve terminals. For example, nitric oxide synthase and cholecystokinin (CCK) have been localized to these nerve terminals, suggesting that nitric oxide and CCK are islet neurotransmitters. CCK was initially demonstrated in 1928 by Ivy and Oldberg as a gut hormone released into the circulation, stimulating gall bladder contraction. It is known today that the peptide is produced in the intestinal I cells, which are situated mainly along the mucosa of the duodenum and the proximal jejunum. Besides its main actions to stimulate gall bladder contraction and exocrine pancreatic secretion, CCK also inhibits gastric emptying and intestinal motility. During the 1970s and 1980s it was demonstrated that CCK is a neuropeptide with localization to both central and peripheral neurons. An interesting central action of CCK is inhibition of food intake. In 1980 it was reported by Dr. Rehfeld and collaborators in Copenhagen that CCK is a neuropeptide in pancreatic islets. The human gene for CCK is located on chromosome 3q12-3pter and consists of three exons. It encodes for a proCCK with a 115-amino acid residue including the 20-amino acid signal peptide, which is posttranslationally modified to generate several different forms of CCK (Fig. 8). The
CCK33 KAPSGRMSIVKNLQNLDPSHRISDRDYMGWMDF» CCKS DYMGWMDF*
Figure 8 Schematic representation of the CCK gene. The first exon and the 5'-end of the second exon encode the signal peptide. Exon 2 also encodes a 20-amino acid spacer peptide in proCCK and, together with the 5'-end of exon 3, the remaining portion of proCCK. At the bottom of the figure are the amino acid sequences of CCK33 (CCK5826-58), CCK8 (CCK5 8 51-58), and CCK4 (CCK5855-58). * indicates a C-terminal NH2 group. Observe that the Y residue in position 27 (in both CCK33 and CCK8) is sulfated.
initial translational product is CCK83, which is further processed by the removal of a 25-amino acid spacer peptide at its N-terminal end, yielding CCK58, the initial stable product of the gene. CCK58 is further processed by N-terminal truncation to CCK variants with 39, 33, 25, 22, 18, 12, 8, 7, 5, and 4 residues, respectively. The processing mechanisms and the function of all of these intermediates or CCK forms are still not established. However, CCK33 and CCK8 appear to be the main forms of CCK in circulation, whereas in the neurons most evidence favors the smaller CCK forms, like CCK4, as the main products that therefore probably function as neuro-transmitters. The processing of proCCK in the nerves has not been examined in such detail as in the gut, although it has been revealed that it is the same CCK gene that is expressed in nerve cell bodies as in the I cells.
In the pancreatic islets, CCK has been shown to potently stimulate insulin secretion, and this has been demonstrated under a variety of experimental conditions. This action may be of physiological importance after food intake, when the circulating levels of CCK are increased. It is unlikely, however, that CCK is of physiological importance after food intake, because the circulating levels of CCK achieved after food intake are lower than those required for stimulation of insulin secretion and because inhibition of CCK release or action does not affect meal-induced insulin secretion in humans. Therefore, the main function of CCK in relation to the pancreatic islets is probably as a neurotransmitter. However, the role of these "other" nerves in the regulation of insulin secretion, particularly in relation to the influence of the three main branches, is not known. CCK has also been shown to stimulate glucagon secretion, although this has not been studied in such great detail as its effects on insulin secretion.
Two different types of CCK receptors have been described, both of which are of the G-protein-coupled, seven transmembranous domain type linked to the activation of PLC. The CCKA receptor gene is located on chromosome 4p15.1-p15.2, whereas the CCKB receptor gene is located on chromosome 11p15.4-p15.5. The CCKa receptor type consists of 428 amino acids and is expressed in the gall bladder smooth muscle cells, pancreatic acinar cells, gastrointestinal muscular cells, and various parts of the brain. This receptor type shows an almost 1000-fold higher affinity for CCK than for gastrin. The CCKB receptor type consists of 447 amino acids and is expressed in the cerebral cortex and other brain areas, gastric parietal cells, ECL cells, and gastrointestinal muscular cells. This receptor type shows equal affinity for CCK and gastrin. In the islets, most studies favor the CCKA receptor subtype as the one that mediates the actions of CCK.
The insulinotropic activation of CCK is mainly mediated by PLC, which stimulates the hydrolysis of phosphoinositides. Phosphoinositide hydrolysis in turn yields the formation of IP3, releasing Ca2+ from intracellular Ca2+ stores to increase the cytosolic concentration of Ca2 + . Consequently, CCK increases the cytosolic concentration of Ca2+ independently from the uptake of extracellular Ca2+, which is accompanied by rapid stimulation of exocytosis and insulin secretion. CCK has also been shown to stimulate the generation of arachidonic acid (AA) through the activation ofPLA2. AA in turn stimulates the exocytosis of insulin through several mechanisms. In contrast, CCK does not seem to increase the islet formation of cAMP. The combined action by CCK to release Ca2+ from intracellular stores to increase the cytosolic concentration of Ca2+ and to stimulate the formation of AA and activate PKC seems to contribute to the insulinotropic action after activation of the CCKA receptors.
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