The localization of the 37-amino acid peptide CGRP to islet nerves was first reported by Rosenfeld and collaborators in 1983 and later confirmed in other laboratories. CGRP was originally described in a medullary thyroid carcinoma cell line, where it was found to be encoded in the same gene as calcitonin. This gene is called the calcitonin complex gene A (CALCA), is located on chromosome 11p15.2-p15.1, and consists of six exons. This gene encodes for two different mRNAs, one being translated to preprocal-citonin and the other to preproCGRP. The N-terminal portions of procalcitonin and proCGRP, consisting of
75 amino acids, are identical in the two prohormones and encoded in exon 3. The remaining part of the 141-amino acid preprocalcitonin is encoded in exon 4, whereas the rest of the 128-amino acid preproCGRP is encoded in exon 5 (Fig. 7). Hence, by alternative splicing, CALCA will be transcribed and translated to either procalcitonin or proCGRP. This alternative splicing has turned out to be tissue-specific. Later, an additional gene that also encodes for CGRP was described and named calcitonin complex gene B (CALCB). This gene is located at chromosome 11p12-14.2 and encodes for a form of CGRP, which is called b-CGRP and shows a high degree of similarity to the a-CGRP that is encoded in CALCA. In addition, two other genes have been grouped together with CALCA and CALCB to a calcitonin gene family. These other genes are the calcitonin complex pseudogene (CALCP), the function of which is yet unknown, and the islet amyloid polypeptide (IAPP) gene, located at chromosome 12p13.2-12.1 and encoding for IAPP. CGRP consists of 37 amino acids with a high degree of identity between species. The two forms of CGRP, a and b, differ in three amino acids in humans and in one amino acid in rats. CGRP is also structurally related to IAPP, calcitonin, and adrenomedullin. CGRP has been demonstrated to be a ubiquitously distributed neuropeptide with localization in both the central nervous system and peripherally. It seems to be mainly localized to sensory nerves. A multitude of biological
haCGRP acdtatcvthrlagllsrsggvvknnfvptnvgskaf* hfiCGRP acntatcvthrlagllsrsggmvksnfvptnvgskaf* hIAPP kcntatcatqrlanflvhssnn fga1 lsstnvgsnt y* hcalcitonin cgnlstcmlgtytqdfnkfhtfpqtaigvgap*
Figure 7 Schematic representation of the calcitonin complex gene A (CALCA) and proCGRP. The first exon is non-encoding, exon 2 encodes the signal peptide, exon 3 encodes the N-terminal extension peptide of proCGRP, which is identical to the corresponding N-terminal extension peptide of procalcitonin, exon 4 encodes for the remaining portion of procalcitonin, exon 5 encodes the remaining portion of proCGRP, and exon 6 is noncoding. At the bottom of the figure are the amino acid sequences of human a- and b-CGRP, human IAPP, and human calcitonin. * indicates a C-terminal NH2 group.
actions of CGRP have been demonstrated in a variety of experimental conditions, and these include the induction of vasodilatation, increase in tissue blood flow, activation of adrenergic nerve outflow, inhibition of gastric acid and thyroid hormone secretion, and stimulation of exocrine pancreatic secretion.
CGRP nerves are also localized to the pancreas, where they are scattered throughout the parenchyma with particular density along small blood vessels and within the islets. Exogenous administration of the peptide under various experimental conditions leads to the inhibition of insulin secretion and stimulation of glucagon secretion. The physiological relevance of the CGRP nerves has been studied in animals treated with capsaicin, which destroys C-fibers and is followed by marked reduction of the CGRP nerves in the pancreatic islets. In capsaicin-treated mice, the glucagon response to neuroglycopenia induced by the glucose analog, 2-deoxyglucose (2-DG) is inhibited and the glucose recovery from insulin-induced hypoglycemia is impaired, suggesting a stimulatory role of the sensory fibers on glucagon secretion. Furthermore, insulin secretion is augmented after capsaicin, suggesting a tonic inhibitory influence of the sensory nerves on the b cells. These studies therefore suggest a physiological importance for CGRP nerves in the regulation of both insulin and glucagon secretion.
CGRP acts through the calcitonin receptor-like receptor (CRLR) or the calcitonin receptor (CTR). Both of these receptors show affinity for IAPP, calcitonin, and adrenomedullin. Three different receptor-activity-modifying proteins (RAMPs) seem to govern the specificity of the receptors for these ligands. For example, elegant studies by Sexton and collaborators in Melbourne have shown that the RAMP1-transported CRLR is a CGRP receptor, whereas RAMP2- or RAMP3-transported CRLR is an adre-nomedullin receptor. They also demonstrated that IAPP binding is more related to RAMP-transported CTR. These findings suggest an interesting mode of regulation of cellular activity. Of particular interest for islet physiology is the relation between CGRP and IAPP, both in terms of sequence similarity and in terms of similarities in receptors activated by the peptides. IAPP is a b-cell peptide with a potential role in diabetes pathophysiology because it both inhibits insulin secretion and forms amyloid fibrils, which are common in islets of subjects with type 2 diabetes. It should also be emphasized that, in some species, CGRP seems to be expressed in the islet endocrine cells. Thus, in rat islets, CGRP is found in the D cells. The role of islet cellular CGRP is not known.
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