PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Receptors, Islet Amyloid Polypeptide”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2001

Amylin receptor agonists: a novel pharmacological approach in the management of insulin-treated diabetes mellitus.

Amylin is a peptide hormone which is co-secreted with insulin from the pancreatic beta-cell. Type 1 diabetic individuals and some Type 2 diabetic individuals are characterised by amylin deficiency. Animal experiments have revealed several actions of amylin on intermediary metabolism, of these some have been demonstrated to be of potential physiological relevance in humans. In particular amylin appears to have important actions in controlling prandial glucose homeostasis. The peptide hormone inhibits postprandial glucagon secretion and delays gastric emptying thereby modifying postprandial hyperglycaemia in diabetic individuals which presumably adds to overall glycaemic control without a concomitant increase in the number of severe hypoglycaemic episodes. Moreover, amylin acts as a satiety agent. Amylin replacement may therefore improve glycaemic control in diabetes mellitus. However, human amylin exhibits physicochemical properties predisposing the peptide hormone to aggregate and form amyloid fibres, which makes it unsuitable for pharmacological use. A stable analogue, pramlintide, with actions and pharmacokinetic and pharmacodynamic properties similar to the native peptide has therefore been developed. The efficacy and safety of pramlintide administration to diabetic individuals have been tested in a large number of clinical trials. It is the aim of this review to describe possible (patho)physiological actions of amylin as demonstrated in animal and human models, to discuss the background for potential amylin (analogue) replacement in diabetes mellitus and to review results from clinical trials with the amylin receptor analogue pramlintide.

Amyloid↗
PubMed1997

Role of amylin in nutrient intake - animal studies.

The pancreatic hormone amylin is co-secreted with insulin by beta-cells in response to nutrient intake. Studies performed in experimental animals have provided evidence that amylin may have several effects associated with carbohydrate metabolism. Amylin is a potent inhibitor of gastric emptying. This effect appears to require an intact vagus nerve and it is over-ridden by hypoglycaemia. These observations, coupled with the identification of putative amylin receptors in the area postrema of the hindbrain (a region implicated in the regulation of gastric motility) suggest that the effects of amylin on gastric emptying are mediated, at least in part, by the central nervous system. There is also evidence that amylin acts to inhibit food intake, an action which is distinct from its effects on gastric emptying. In addition, amylin has been shown to inhibit amino acid-stimulated glucagon secretion, suggesting that it may reduce endogenous glucose production in the postprandial period.

Amyloid↗
PubMed1994

Islet amyloid polypeptide: does it play a pathophysiological role in the development of diabetes?

There is suggestive evidence that amylin acts physiologically in an autocrine manner within the islet to restrain insulin secretion, but conversely there is little indication that this action of amylin plays any role in the development of NIDDM. Deposition of amylin within pancreatic islets is a feature in patients with NIDDM but is of sufficient degree to disrupt beta-cell function in only a small minority of individuals. Current evidence suggests that amylin does not have any physiologically important extra-islet metabolic effects. The potential exists for the development of amylin antagonists as pharmacological agents to enhance insulin secretion in NIDDM but antagonism of systematic CGRP would need to be avoided. There is little, if any, indication that either replacement of amylin or treatment with amylin agonists are likely to have any beneficial role in patients with IDDM.

Amyloid↗
PubMed1996

Amylin mobilizes [Ca2+]i and stimulates the release of pancreatic digestive enzymes from rat acinar AR42J cells: evidence for an exclusive receptor system of amylin.

Amylin dose-dependently stimulated the secretion of amylase and cholesterol esterase from rat pancreatic acinar AR42J cells. The biochemical basis of this action was investigated using fura-2-loaded AR42J cells. Amylin increased intracellular free calcium. [Ca2+]i, in a dose-dependent manner. The Ca2+ signal persisted even in Ca(2+)-free medium, suggesting mobilization from intracellular stores rather than influx. Consistently, thapsigargin abolished amylin-induced responses, suggesting that Ca2+ is released from an inositol 1,4,5-triphosphate (IP3)-sensitive pool. This was confirmed by the finding that amylin elevated IP3 levels. AR42J cells pretreated with amylin did not respond to amylin, suggesting that the receptors mediating this response undergo homologous desensitization. However, pretreatment with related peptides, calcitonin gene-related peptide (CGRP) and salmon calcitonin, did not diminish [Ca2+]i mobilization by amylin. CGRP and calcitonin also failed to mobilize [Ca2+]i even at 10 microM. These results suggests that the stimulatory effects of amylin on pancreatic digestive enzyme secretion from AR42J cells are mediated by a G-protein-linked membrane receptor coupled to IP3-dependent calcium pools.

Amylases↗
PubMedDate not supplied

Role of amylin in insulin secretion and action in humans: antagonist studies across the spectrum of insulin sensitivity.

BACKGROUND: Amylin is a peptide co-secreted with insulin by pancreatic beta-cells. A role for amylin in the pathogenesis of type 2 diabetes mellitus (DM2) has been suggested by in vitro and in vivo studies indicating an effect of amylin to cause insulin resistance and/or inhibit insulin secretion. METHODS: We have determined the effect of endogenous amylin on insulin secretion and insulin action in humans by performing 4-h hyperglycemic clamps during infusion of placebo or a specific amylin receptor antagonist (ARA) in paired, double-blinded, crossover studies. We studied nine healthy lean, ten healthy obese (BMI>27) and ten obesity-matched DM2 subjects. RESULTS: Infusion of ARA alone had no effect on basal insulin, glucose or glucose turnover in any group. Under combined hyperglycemia and ARA infusion, lean subjects displayed a 32% augmentation in insulin levels [AUC 33,565+/-3556 (placebo) to 44,562+/-1379 (ARA) pmol/l/min, p<0.01]. The concomitant increase in glucose disposal rate (GDR) was proportionate, indicating no change in insulin sensitivity (ISI 27.7+/-2.7 vs 27.3+/-2.1, p=NS). In obese subjects, basal insulin and the rise in insulin during the clamp were greater (AUC I 44% increase from 82,054+/-15 407 to 117,922+/-27,085, p<0.01), and also accompanied by a proportionate rise in GDR reflecting an unchanged insulin sensitivity (ISI 12.1+/-2.9 vs 10.8+/-3.0, p=NS). In lean and obese subjects, the C-peptide response to hyperglycemia was also augmented by ARA (p=0.007). No effect of ARA on insulin secretion or action was observed in diabetic subjects. CONCLUSIONS: The present data are consistent with an effect of endogenous amylin on the beta-cell to modulate and/or restrain insulin secretion, and indicate that endogenous amylin does not affect insulin action. These observations provide the first human evidence that amylin plays a role in the modulation of insulin secretion.

Adult↗
PubMed1993

Islet amyloid polypeptide: a review of its biology and potential roles in the pathogenesis of diabetes mellitus.

Islet amyloidosis (IA) is the principal lesion in the endocrine pancreas of human beings with non-insulin-dependent diabetes mellitus (NIDDM) and in the similar forms of diabetes mellitus in domestic cats and macaques. As such, the delineation of the pathogenesis of this form of amyloidosis may be crucial to the understanding of the development and progression of NIDDM. Islet amyloid polypeptide (IAPP) is a recently discovered polypeptide that is the principal constituent of IA in human beings, cats, and macaques. IAPP is produced by the pancreatic beta-cells and is co-packaged with insulin in the beta-cell secretory vesicles. Immunohistochemical and physiologic evidence supports the notion that the beta-cells are heterogenous with respect to their relative contents of insulin and IAPP. Therefore, although IAPP is co-secreted with insulin in response to a variety of well-known insulin secretagogues, the molar ratio of these two proteins that is released from the islets may vary, depending upon the glucose concentration and prevailing metabolic milieu. IAPP is highly conserved among mammalian species and has about 45% homology to another neuropeptide, calcitonin gene-related peptide. IAPP is encoded by a single-copy gene located, in the human being, on chromosome 12. IAPP is expressed as a 93 (murine)-89 (human)-amino acid prepropolypeptide that is processed enzymatically, resulting in the removal of amino- and carboxy-terminal propeptide segments. The 20-29 region of the IAPP molecule is most important in the ability of IAPP to form amyloid fibrils. The role of IAPP and IA in the pathogenesis of human NIDDM and similar forms of diabetes mellitus in cats and macaques may involve several possible mechanisms, including 1) direct physical/chemical damage to beta-cells, resulting in necrosis and loss of functional islet tissue, 2) biologic activities of IAPP that oppose those of insulin or abnormally suppress insulin secretion, and 3) interference by IA deposits of passage of insulin out of beta-cells and/or entrance of glucose and other secretogogues into the islet. The roles of each of these possible mechanisms have yet to be demonstrated. In addition, the physiological significance of the apparent IAPP deficiency in both insulin-dependent diabetes mellitus and NIDDM is currently unknown.

Amino Acid Sequence↗
PubMed2000

Islet amyloid polypeptide (amylin)-deficient mice develop a more severe form of alloxan-induced diabetes.

To examine whether islet amyloid polypeptide (IAPP), other than through amyloid formation, may be of importance in diabetes pathogenesis, IAPP-deficient mice (IAPP(-/-)) were challenged with alloxan (day 0). Diabetes in IAPP(-/-) mice was more severe at day 35, indicated by greater weight loss; glucose levels were higher in alloxan-treated IAPP(-/-) mice, whereas insulin levels were lower, indicating a greater impairment of islet function. Accordingly, glucose levels upon intravenous glucose challenges at days 7 and 35 were consistently higher in alloxan-treated IAPP(-/-) mice. At day 35, insulin mRNA expression, but not beta-cell mass, was lower in untreated IAPP(-/-) mice. Yet, upon alloxan administration, beta-cell mass and numbers of beta-cell-containing islets were significantly more reduced in IAPP(-/-) mice. Furthermore, they displayed exaggerated beta-cell dysfunction, because in their remaining beta-cells, insulin mRNA expression was significantly more impaired and the localization of glucose transporter-2 was perturbed. Thus the lack of IAPP has allowed exaggerated beta-cell cytotoxic actions of alloxan, suggesting that there may be beneficial features of IAPP actions in situations of beta-cell damage.

Amyloid↗
PubMed1994

Calcitonin gene-related peptide and islet amyloid polypeptide stimulate insulin secretion in RINm5F cells through a common receptor coupled to a generation of cAMP.

The question as to whether the homologous peptides CGRP and IAPP can regulate insulin secretion in RINm5F cells was addressed. Chicken CGRP displayed a reproducible inhibitory effect on insulin secretion within 0.1 and 1 nM concentrations and a stimulatory effect at higher concentrations. The maximal stimulatory effects on insulin secretion were obtained with 1.0 microM of chicken CGRP (cCGRP), human alpha-CGRP (h alpha-CGRP) and human IAPP (hIAPP) which caused 246 +/- 22, 302 +/- 63 and 224 +/- 14 percent increases of control levels, respectively (p < 0.001). Similarly, maximal accumulations of cAMP were obtained with 1.0 microM of cCGRP, h alpha-CGRP and hIAPP with the respective percent increases of control levels of 587 +/- 24, 436 +/- 41 and 410 +/- 25 (p < 0.005). Thus the stimulatory effects on insulin secretion in RINm5F cells by cCGRP, h alpha-CGRP and hIAPP appear to be mediated by the cAMP pathway. Chicken CGRP, the most potent peptide tested, displayed a correlated dose response stimulation of intracellular cAMP and insulin release within the concentration range of 10-1000nM. The EC50 values of cCGRP for cAMP accumulation and insulin release were similar (20nM and 10nM respectively). The stimulatory effect of IAPP on cAMP was not additive with that of cCGRP suggesting that IAPP action was mediated by CGRP receptors. This hypothesis was further sustained by a preferential inhibition of 125I[His]h alpha-CGRP binding to RINm5F cells by cCGRP as compared to IAPP. We conclude that CGRP and IAPP, through a direct action on a chicken CGRP preferring receptor present in beta cells, stimulated insulin by a cAMP mediated pathway.

Amyloid↗
PubMed1995

Receptors for calcitonin, calcitonin gene related peptide, amylin, and adrenomedullin.

Calcitonin, calcitonin gene related peptide, amylin, and adrenomedullin are structurally related polypeptides characterized by a six or seven amino acid ring structure linked by a disulfide bridge and an amidated C-terminus. They exhibit overlapping biological actions as a result of cross-reactivity between the different receptors. In this article, the respective receptors and G-protein-coupled postreceptor events are reviewed in relation to some of the biological actions of the peptides.

Animals↗
PubMed2000

The molecular pharmacology of CGRP and related peptide receptor subtypes.

Calcitonin gene-related peptides (alpha and beta isoforms), better known as CGRPalpha and CGRPbeta, were isolated twenty years ago. In fact, these were the first peptides to be characterized using a molecular cloning strategy, which is not the traditional approach of biochemical extraction and purification. Paradoxically, progress in the characterization of CGRP receptor subtypes has been extremely slow as a result of difficulties in their cloning and the lack of selective receptor subtype agonists and antagonists. However, exciting progress has been made overthe pasttwo years and is briefly reviewed here.

Amino Acid Sequence↗
PubMed2005

Receptor pharmacology.

Despite clear evidence for a distinct amylin pharmacology and localization of such pharmacology to sites such as the nucleus accumbens,efforts to clone an amylin receptor were fruitless for over a decade. This enigma led many to doubt the status of amylin as a bona fide hormone. Yet it became apparent during those cloning efforts that, whatever the amylin receptor was, it was somehow similar to a calcitonin receptor. The enigma of the amylin receptor was solved following the identification of receptor activity modifying proteins (RAMPs). These single transmembrane spanning molecules, when associated with a calcitonin receptor, altered its pharmacology from calcitonin-preferring to amylin-preferring. With at least two forms of the calcitonin receptor and three forms of RAMP, there is the potential for six subtypes of amylin receptors. Of these, two appear to predominate. The CTa (shorter form) calcitonin receptor, dimerized with RAMP1 [amylin 1 (a) receptor], appears to represent binding sites at the nucleus accumbens and the subfornical organ. Binding sites at area postrema appear to be composed of CTa + RAMP3 [amylin3 (a) receptors]. Thus far, RAMP proteins have been associated in vivo only with the CT/CLR receptor system. It is presently unknown whether RAMPs are more general modulators of receptor function, dynamically modifying responsivity with time or across other receptor classes. The largest and first identified amylin-binding field was in the nucleus accumbens. The function of these receptors is yet undetermined, but because the nucleus accumbens is within the blood-brain barrier, the cognate ligand is unlikely to be circulating amylin. Dense amylin binding is present at the circumventricular organs, including the subfornical organ, the organum vasculosum lateralis terminalis (OVLT), and the area postrema. There is no diffusional (blood-brain) barrier at these structures, so they most likely respond to circulating (beta-cell-derived) amylin. Despite pharmacological evidence of amylin sensitivity in several peripheral tissues, selective amylin binding outside of the brain is observed only in the renal cortex. The newly designated amylinomimetic drug class was defined on the basis of its unique pharmacology prior to the molecular characterization of amylin receptors. Currently, the class includes any agent that acts as antagonist at characterized amylin receptors. Several peptides, typically analogs of truncated salmon calcitonin, have been developed as potent and selective amylin antagonists and have been useful in identifying amylinergic responses. Of these, AC187 (30Asn32Tyr[8-32]sCT; Amylin Pharmaceuticals Inc.) is particularly selective and potent, and has been most often cited in studies using amylin antagonists. Antagonism of a response with an order of potency of AC187> AC66 > CGRP[8-37] is suggestive that it is mediated via amylin receptors. Activation of a response with salmon calcitonin (sCT) > amylin >calcitonin gene-related peptide (CGRP) > mammalian CT suggests activation via the amylinl (a) receptor, while sCT = amylin >> CGRP >mammalian CT suggests activation via amylin3 (a) receptors. Absence of response to other ligands (e.g., adrenomedullin) is useful for excluding certain pharmacologies.

Animals↗
PubMed1997

The selectivity and structural determinants of peptide antagonists at the CGRP receptor of rat, L6 myocytes.

1. Potency orders were determined for a series of agonists and antagonists on the calcitonin gene-related peptide (CGRP) receptor of rat L6 myocytes. The agents tested were all shown to have been active against CGRP, amylin or adrenomedullin receptors. 2. AC187 had a pIC50 of 6.8 +/- 0.10, making it 14 fold less potent as an antagonist than CGRP8-37 (pIC50, 7.95 +/- 0.14). Amyline8-37 was equipotent to AC187 (pIC50, 6.6 +/- 0.16) and CGRP19-32 was 3 fold less potent than either (pIC50, 6.1 +/- 0.24). 3. [Ala11]-CGRP8-37 was 6 fold less potent than CGRP8-37, (pIC50, 7.13 +/- 0.14), whereas [Ala18]-CGRP8-37 was approximately equipotent to CGRP8-37 (pIC50, 7.52 +/- 0.15). However, [Ala11,Ala18]-CGRP8-37 was over 300 fold less potent than CGRP8-37 (pIC50, 5.30 +/- 0.04). 4. [Tyr0]-CGRP28-37, amylin19-37 and adrenomedullin22-52 were inactive as antagonists at concentrations of up to 1 microM. 5. Biotinyl-human alpha-CGRP was 150 fold less potent than human alpha-CGRP itself (EC50 values of 48 +/- 17 nM and 0.31 +/- 0.13 nM, respectively). At 1 microM, [Cys(acetomethoxy)2,7]-CGRP was inactive as an agonist. 6. These results confirm a role for Arg11 in maintaining the high affinity binding of CGRP8-37. Arg18 is of less direct significance for high affinity binding, but it may be important in maintaining the amphipathic nature of CGRP and its analogues.

Amino Acid Sequence↗
PubMed2004

Amylin receptors: molecular composition and pharmacology.

Several receptors which bind the hormone AMY (amylin) with high affinity have now been identified. The minimum binding unit is composed of the CT (calcitonin) receptor at its core, plus a RAMP (receptor activity modifying protein). The receptors have been named AMY(1(a)), AMY(2(a)) and AMY(3(a)) in accordance with the association of the CT receptor (CT((a))) with RAMP1, RAMP2 and RAMP3 respectively. The challenge is now to determine the localization and pharmacological nature of each of these receptors. Recent attempts to achieve these aims will be briefly discussed.

Animals↗
PubMed2005

Pharmacological discrimination of calcitonin receptor: receptor activity-modifying protein complexes.

Calcitonin (CT) receptors dimerize with receptor activity-modifying proteins (RAMPs) to create high-affinity amylin (AMY) receptors, but there is no reliable means of pharmacologically distinguishing these receptors. We used agonists and antagonists to define their pharmacology, expressing the CT(a) receptor alone or with RAMPs in COS-7 cells and measuring cAMP accumulation. Intermedin short, otherwise known as adrenomedullin 2, mirrored the action of alpha CGRP, being a weak agonist at CT(a), AMY(2a), and AMY(3a) receptors but considerably more potent at AMY(1a) receptors. Likewise, the linear calcitonin gene-related peptide (CGRP) analogs (Cys(ACM)(2,7))h alpha CGRP and (Cys(Et)(2,7))h alpha CGRP were only effective at AMY(1a) receptors, but they were partial agonists. As previously observed in COS-7 cells, there was little induction of the AMY(2a) receptor phenotype; thus, AMY(2a) was not examined further in this study. The antagonist peptide salmon calcitonin(8-32) (sCT(8-32)) did not discriminate strongly between CT and AMY receptors; however, AC187 was a more effective antagonist of AMY responses at AMY receptors, and AC413 additionally showed modest selectivity for AMY(1a) over AMY(3a) receptors. CGRP(8-37) also demonstrated receptor-dependent effects. CGRP(8-37) more effectively antagonized AMY at AMY(1a) than AMY(3a) receptors, although it was only a weak antagonist of both, but it did not inhibit responses at the CT(a) receptor. Low CGRP(8-37) affinity and agonism by linear CGRP analogs at AMY(1a) are the classic signature of a CGRP2 receptor. Our data indicate that careful use of combinations of agonists and antagonists may allow pharmacological discrimination of CT(a), AMY(1a), and AMY(3a) receptors, providing a means to delineate the physiological significance of these receptors.

Amino Acid Sequence↗
PubMed2006

Determinants of 1-piperidinecarboxamide, N-[2-[[5-amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) affinity for calcitonin gene-related peptide and amylin receptors--the role of receptor activity modifying protein 1.

1-Piperidinecarboxamide, N-[2-[[5-amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS), a calcitonin gene-related peptide (CGRP) receptor antagonist, can alleviate the symptoms of migraine and is highly selective for CGRP over adrenomedullin (AM) receptors. These receptors are heterodimers of the calcitonin receptor-like receptor (CL) and receptor activity modifying proteins (RAMPs), with the pharmacological properties determined by the RAMP subunit. BIBN4096BS-sensitive CGRP(1) receptors are CL/RAMP1, whereas BIBN4096BS-insensitive AM receptors are CL/RAMP2 or CL/RAMP3 (AM(1) and AM(2), respectively), implicating RAMP1 in conferring BIB-N4096BS sensitivity. Because calcitonin receptors [CT((a))] also interact with RAMP1 [AMY(1(a)) receptors], BIBN4096BS could also have affinity for these receptors. To test this, receptors were transfected into COS-7 cells and agonist-stimulated cAMP levels measured in the presence and absence of antagonists. We found that AMY(1(a)) receptors were approximately 150-fold less sensitive to BIBN4096BS antagonism than CGRP(1) receptors. In contrast, AMY(3(a)) [CT((a))/RAMP3] or AM(2) receptors were not sensitive to BIBN4096BS antagonism. We investigated Trp74 in RAMP1, a residue implicated in the species selectivity of BIBN4096BS. BIBN4096BS affinity was reduced at AMY(1(a)) and CGRP(1) receptors when this residue was mutated to lysine or alanine. The equivalent residue in RAMP3, Glu74, when mutated to tryptophan (E74W), induced BIBN4096BS sensitivity at AM(2) and AMY(3(a)) receptors. It is interesting that a selective reduction in AM potency was observed at E74W AM(2) receptors, implicating this residue in AM interactions with this receptor. These data support the importance of Trp74 in RAMP1 in the interaction of BIBN4096BS with CGRP(1) and AMY(1(a)) receptors and identified Glu74 in RAMP3 as the first amino acid in RAMP important for agonist interactions with calcitonin-family receptors.

Amino Acid Sequence↗
PubMed1995

Comparative distribution of receptors for amylin and the related peptides calcitonin gene related peptide and calcitonin in rat and monkey brain.

The distribution of amylin receptors (125I-labelled rat amylin) in brains of rat and monkey were mapped and compared with the distribution of receptors for calcitonin (CT) (125I-labelled salmon CT) and calcitonin gene related peptide (CGRP) (rat, 125I-labelled rat CGRP alpha; monkey, 125I-labelled human CGRP alpha. In rat, amylin receptors were discretely distributed with the highest receptor densities found in mid-caudal accumbens nucleus, parts of the bed nucleus of the stria terminalis, amygdala, and hypothalamus. Moderate to high densities of binding also occurred in the area postrema, subfornical organ, vascular organ of the lamina terminalis, locus ceruleus, dorsal raphe, and caudal solitary tract nucleus. In monkey, the distribution of amylin binding sites was similar, although the highest densities of receptors were in the hypothalamus, with relatively fewer sites present in the accumbens nucleus. In rat, the distribution of amylin receptors formed a subset of the receptor distributions for 125I-labelled salmon CT and 125I-labelled rat CGRP alpha. In contrast, in monkey, although the amylin receptors again formed a subset of the binding sites identified with 125I-labelled salmon CT, there was very little overlap with the pattern of CGRP receptor distribution. This suggests that the specificity profile of amylin receptors in primates differs from that of amylin receptors in the rat, with CGRP alpha having relatively lower affinity for the primate amylin receptors.

Animals↗
PubMed1995

Comparative affinities of human adrenomedullin for 125I-labelled human alpha calcitonin gene related peptide ([125I]hCGRP alpha) and 125I-labelled Bolton-Hunter rat amylin ([125I]BHrAMY) specific binding sites in the rat brain.

Adrenomedullin (ADM) is a recently identified peptide that shows some homology (approximately 25%) with calcitonin gene related peptide (CGRP) and is now considered to be a new member of this peptide family. Because it shares biological effects with CGRP, we evaluated the possible affinity of human adrenomedullin (hADM) for 125I-labelled human CGRP alpha ([125I]hCGRP alpha) binding sites in the rat brain. Moreover, we evaluated the potential existence of cross-reactivity for 125I-labelled Bolton-Hunter rat amylin ([125I]BHrAMY), another member of this peptide family. In all brain areas investigated, hADM only competed with relatively low affinities for both [125I]hCGRP alpha and [125I]BHrAMY binding sites, with IC50 values generally in the high nanomolar-low micromolar range, the lowest affinity being observed for [125I]BHrAMY binding sites. Interestingly, the lowest affinities of hADM against both radioligands were detected in the nucleus accumbens and ventral striatum. These areas are known to be enriched with atypical CGRP - salmon calcitonin - amylin sensitive sites. It thus appears that hADM is unlikely to bind to this atypical site. Moreover, hADM demonstrated limited affinity for either [125I]hCGRP alpha or [125I]BHrAMY binding sites in the rat brain. This suggests that the potential biological effects of ADM in the brain could be mediated through a different class of receptors with higher affinity for this newly isolated peptide.

Adrenomedullin↗