Calcitonin and calcitonin gene-related peptide interact with the same receptor in cultured LLC-PK 1 kidney cells

Wohlwend, Annelise Isabelle; Malmström, Kerstin; Henke, H.; Murer, Heini; Vassalli, Jean‐Dominique; Fischer, Jan A.

doi:10.1016/0006-291x(85)91269-0

Cited by 60 publications

(19 citation statements)

References 13 publications

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“…The three CGRP peptides have also been shown to behave similarly as vasodilators (Brain, Maclntyre & Williams, 1986) and as myotropic agents (Tippins, Marzo, Panico, Morris & Maclntyre, 1986 Furthermore, the fact that calcitonin and CGRP have each been shown to cross-react, but with lower affinity to the other's receptor in many tissues (Goltzmann & Mitchell, 1985;Wohlwend, Malmstrom, Henke, Murer, Vassali & Fischer, 1985) supports this hypothesis. It has recently been emphasized that molecules with relatively little sequence homology can have similar conformational interactions with receptor-membrane complexes (Kaiser & Kezdi, 1984).…”

Section: Discussionmentioning

confidence: 95%

Effects of Peptides From the Calcitonin Genes on Bone and Bone Cells

Zaidi¹,

Bevis²,

Beacham³

et al. 1988

Exp Physiol

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SUMMARYThe calcitonin-calcitonin gene-related peptide (CGRP) gene complex encodes a family of novel peptides -calcitonin, CGRP and katacalcin. Whereas calcitonin is a circulating hormone involved in skeletal maintenance, the physiological function of CGRP still remains unclear. In the present study we have compared the biological activity of CGRP with that of calcitonin using three experimental systems. We have demonstrated that both peptides inhibit bone resorption by active rat osteoclasts and thus lower plasma calcium when injected into young rats. In both respects the CGRP homologues (rat, human a and human /) were found to be 100-to 1000-fold less potent than human calcitonin. The effects of the CGRP peptides and calcitonin were only additive. Human CGRP (ac) also caused a marked dose-dependent elevation of bone cyclic AMP levels in mice, somewhat like calcitonin. Though from our studies it would seem reasonably clear that CGRP is weakly agonistic for the calcitonin receptor on the osteoclast to produce effects on bone resorption and plasma calcium, it is still unclear whether the elevation of bone cyclic AMP simply represents an osteoclastic effect or an additional, more important, effect on osteoblasts. It is highly unlikely that CGRP may exert systemic effects on bone. Nevertheless, the peptide may be an important local regulator of bone cell function.

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Section: Discussionmentioning

confidence: 95%

Effects of Peptides From the Calcitonin Genes on Bone and Bone Cells

Zaidi¹,

Bevis²,

Beacham³

et al. 1988

Exp Physiol

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“…In addition, CT has been used to treat pancreatitis ( 15 ) and peptic ulcer disease ( 16) and to produce centrally mediated analgesia ( 17). It is possible that some of the pharmacological effects of CT may be indirect and attributable to the cross-reaction ofCT with receptors for other hormones that are structurally similar, such as a-or ,B-CT gene-related peptide (CGRP) ( 18,19) or amylin (20). a-CGRP is a product ofthe CT gene produced by differential RNA slicing (21).…”

Section: Introductionmentioning

confidence: 99%

“…fl-CGRP is a product of a separate gene but differs from a-CGRP in only 3 of the 37 amino acids (21)(22)(23). These related ligands most likely interact primarily with their own high affinity receptors to produce hormone-specific effects, but at very high concentrations may also cross-react with the receptors for the other peptides (18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line.

Gorn

Lin²,

Yamin³

et al. 1992

J. Clin. Invest.

190

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A human ovarian small cell carcinoma line (BIN-67) expresses abundant calcitonin (CT) receptors (CTR) (143,000 per cell) that are coupled, to adenylate cyclase. The dissociation constants (Kd) for the CTrRs on these BIN-67 cells is -0.42 nM for salmon Cl and -4.6 nM for human CT. To clone a human CTR (hCTR), a BIN-67 cDNA library was screened using a cDNA probe from a porcine renal CTR (pClR) that we recently cloned. One positive clone of 3,588 bp was identified. Transfection of this cDNA into COS cells resulted in expression of receptors with high affinity for salmon CT (Kd = -0.44 nM) and for human CT (Kd = -5.4 nM). The expressed hCTR was coupled to adenylate cyclase. Northern analysis with the hCTR cDNA probe indicated a single transcript of -4.2 kb. The cloned cDNA encodes a putative peptide of 490 amino acids with seven potential transmembrane domains. The amino acid sequence of the hCTR is 73% identical to the pCTR, although the hCTR contains an insert of 16 amino acids between transmembrane domain I and II. The structural differences may account for observed differences in binding affinity between the porcine renal and human ovarian CI'Rs. The CTRs are closely related to the receptors for parathyroid hormoneparathyroid hormone-related peptide and secretin; these receptors comprise a distinct family of G protein-coupled seven transmembrane domain receptors. Interestingly, the hClTR sequence is remotely related to the cAMP receptor of Dictyostehlum discoideum (21% identical), but is not significantly related to other G protein-coupled receptor sequences now in the data bases. (J.

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“…Further, calcitonin-gene-related peptide (CGRP), a peptide alternatively processed from the calcitonin gene, is known to bind the calcitonin receptor of LLC-PK1 [16]. CGRP and ultimobranchial CTs must share a common sequence as the receptor-binding region.…”

Section: Discussionmentioning

confidence: 99%

Structure/activity relationship of eel calcitonin

Inoue

Shikano

Komatsu

et al. 1991

European Journal of Biochemistry

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A series of analogs of eel calcitonin (eCT) was synthesized according to a newly devised scheme, 'the insertioninactivation method', to clarify the structure/activity relationship of a given peptide. This method consists of two steps: the deletion of a residue of the peptide is first chosen and then a series of analogs with the residue reinserted into serial positions is synthesized and biological activities are assessed in each step.An analog lacking Lysl8 (dK), selected as a deleted analog for the first step, showed marked loss of activities determined by inhibition of L251-eCT binding, growth inhibition, and cAMP production in a porcine kidney cell line LLC-PKI. Activities of a set of 20 analogs with the reinserted lysine residue at serial positions from 12 to 32 (K12 -K32) were then evaluated. The results showed the following three patterns of the expression of activities according to the position of the reinsertion: (a) analogs K12-Kl6 (positions 12-16) and K25 (position 25) showed lower activities than eCT in all assays; (b) K17-K24 (positions 17-24) showed slightly lower activities than eCT in the receptor binding and the growth inhibition and similar level in cAMP production; (c) K26 -K32 (positions 26-32) showed considerably lower activities in the former two assays and slightly lower activity in cAMP production. Further, analogs considerably less active than eCT showed unchanged a-helix contents and destroyed amphiphilicity by the insertion of a lysine residue, indicating that amphiphilicity is one of important factors for expressing the activity.The results obtained here lead to a conclusion on the significance of each region of eCT molecule as follows: (a) the presence of Lysl8 is necessary for the complete expression of biological activity; (b) the length of amphiphilic a-helix to be required for the activity is at most 10 residues ranging from position 8 to position 17; (c) the receptor binding region is located within 9 residues ranging from position 24 to position 32.Calcitonin (CT) is a calcium-regulating peptide hormone found in many vertebrate species. The common structure of CT is 32 amino acid residues with a seven-residue cyclic loop formed by a disulfide bond between cysteines at positions 1 and 7 and prolinamide at the carboxyl terminal. CTs are categorized into three groups by both sequence and biological potency: ultimobranchial CTs [salmon CT (sCT), eel CT (eCT), and chicken CT]; artiodactyl CTs [porcine CT (pCT), bovine CT, and ovine CT]; and primate or rodent CTs (human CT and rat CT) [l]. Among them, CTs of ultimobranchial origin are the most potent in hypocalcaemic activity determined in human and rat [l -41. eCT and sCT are also known to increase the cAMP production in mammalian primary and established cells [4-61 and to inhibit the growth of established cell lines [6, 71. The correlation between in vivo hypocalcaemic activity and the in vitro activity such as the cAMP production and the growth inhibition is not clear.Many studies on the structure/activity relationship in ultimobr...

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Calcitonin and calcitonin gene-related peptide interact with the same receptor in cultured LLC-PK 1 kidney cells

Cited by 60 publications

References 13 publications

Effects of Peptides From the Calcitonin Genes on Bone and Bone Cells

Effects of Peptides From the Calcitonin Genes on Bone and Bone Cells

Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line.

Structure/activity relationship of eel calcitonin

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