Calcitonin gene related peptide.

Calcitonin gene related peptide (CGRP) gets its odd name from the way it was first identified; its existence was predicted from molecular cloning studies ofthe calcitonin gene. It is a 37 amino acid peptide formed from the preprocalcitonin gene on chromosome 11. 2 The big primary RNA transcript produces two different peptides by alternative splicing. In thyroid C cells the gene produces procalcitonin; in neural tissues it produces proCGRP. The peptide itselfwas first isolated from a human medullary carcinoma.34Further work has shown that an entirely separate second peptide, termed 1-calcitonin gene related peptide, is produced in rather smaller amounts by an encoding gene also located on chromosome 1 1, but in this case with no associated calcitonin-like sequence.57 While the peptides bear little structural similarity to calcitonin they do bind (poorly) to its receptor, suggesting that they are related by an evolutionary ancient gene duplication.8 Both forms show a high degree of evolutionary conservation,9 differing between themselves by one amino acid in rats'0 and three in humans. " What, then, does calcitonin gene related peptide do? Firstly, it is an important neurotransmitter in the peripheral sensory nervous system. It is found in the same primary sensory neurones that synthesise substance P, but the peptide is usually made in greater amounts. Neurones in the dorsal root ganglia synthesise the peptide for transport both centrally and peripherally. '21 3 Calcitonin gene related peptide may be found in most organ systems -and its concentration generally reflects the density of the perivascular neuronal network. '4-16 Lower amounts of the peptide are synthesised in motor neurones. '2 In the gut the I form of the peptide is made by neurones of the enteric nervous system. ' Expression of calcitonin gene related peptide has been mapped to many discrete nuclei and tracts in the brain, with particularly high concentrations being present in the hypothalamus and locus caeruleus and lesser amounts in the cerebrum and subcortical nuclei. ' 119 Binding of calcitonin gene related peptide to receptors in the brain generally matches peptide distribution, except in the cerebellum, where binding is higher, and in the pituitary, where it is much lower. '0202' While in most tissues the originally described (or oa) peptide predominates, the human pituitary is an extremely rich source of the (3 form production and storage. 18 22 Calcitonin gene related peptide is also found in some tumours, such as Ewing's carcinoma and small cell carcinoma of the lung,23 21 but it has proved a disappointing marker for medullary carcinoma of the thyroid.25 Syndromes of altered production of the peptide have yet to be defined. Does calcitonin gene related peptide function as a hormone as well as a neurotransmitter? As yet there is no evidence to support this concept, though multiple molecular forms of the peptide have been reported in normal human plasma.2627 Concentrations of the peptide in the plasma are raised in pregnancy" and, interestingly, receptors for the peptide have been identified in the placenta itself.29 Given its ubiquitous distribution the peptide has been postulated to exert many different functions in different tissues, but a hormonal function seems unlikely. Historically, peptides in neural tissue have been seen merely as modulators of nerve impulse transmission. Calcitonin gene related peptide, however, can act directly as a neurotransmitter or as a trophic factor-for example, promoting the development and growth ofdopamine containing neurones in the olfactory bulb.30 It may also regulate the number of acetylcholine receptors at the neuromuscular junction.3'"-" Interestingly, Gibson et al have reported a loss of motoneurones that stain positive for calcitonin gene related peptide in the ventral spinal cord in motor neurone disease.35 By contrast, a recent study of the calcitonin gene related peptide content of brain and spinal cord in Alzheimer-type dementia (characterised by severe neuronal atrophy) found no difference from normal in the distribution pattern.36 Outside the central nervous system the peptide plays an important part in the control of regional blood flow-it is, indeed, the most powerful vasodilator yet identified.37 The factors that influence the release of calcitonin gene related peptide from perivascular nerves are unclear, and it has proved difficult to define its physiological importance in the absence of specific receptor blocking agents. A deficiency of the peptide has, however, been postulated as relevant in Raynaud's phenomenon. " Laboratory experiments have provided us so far with only a partial view of the likely importance of calcitonin gene related peptide. Certainly it seems active in inflammatory responses, where it acts in synergy with substance P; in experiments these two peptides together can mimic the neural mediated inflammatory response.39 Calcitonin gene related peptide primarily promotes vasodilatation-with, unlike substance P, little direct effect on microvascular permeability. "-" In the heart the highest concentrations of receptors for the peptide are in the main coronary arteries. The numbers of binding sites are reduced in areas of atheroma, possibly predisposing these vessels to spasm and thrombosis.4' Intracoronary infusion studies in humans show that the peptide potently dilates epicardial vessels and delays the onset of cardiac ischaemia after systemic administration. ' ' Though calcitonin gene related peptide has not been shown to have a selective action on basal cerebral blood flow, objective improvement in neurological deficit was seen in nine out of 15 patients during an infusion with the peptide after surgery for subarachnoid haemorrhage, presumably by relieving vasospasm.47 Not surprisingly, in the lung calcitonin gene related peptide causes endothelium independent vasodilatation of small pulmonary vessels through specific receptors,48 but it is also a potent bronchoconstrictor.49 This latter observation has led to the suggestion that the peptide may play a part in asthma.50 5' Calcitonin gene related peptide and amylin (IAPP, the recently isolated peptide component of pancreatic amyloid found in human and animal models of type II diabetes) share a 46% sequence homology, express common epitopes, and are potent inhibitors of basal and insulin stimulated glycogen synthesis in skeletal muscle.52 53Calcitonin gene related peptide is thus theoretically capable of providing metabolic fuels for muscle consumption during active contraction. Giving calcitonin gene related peptide in pharmacological doses in humans results in hypotension, reflex tachycardia, release of catecholamines,5455 and weak inhibition of gastric acid secretion,56 but no alteration in plasma calcium concentrations.55 The multiplicity of actions of the two calcitonin gene related peptides gives an insight into the complex nature of the body's control systems and underlies the extent ofour lack of knowledge of such systems. The development of specific antagonists is under way; when these are available the next step will be further to define the role of the cc and ( forms and