Amylin: Pharmacology, Physiology, and Clinical Potential

Hay, Debbie L.; Chen, Steve; Lutz, Thomas; Parkes, David G.; Roth, Jonathan D.

doi:10.1124/pr.115.010629

Cited by 289 publications

(351 citation statements)

References 296 publications

(421 reference statements)

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“…The potent CT receptor agonist salmon calcitonin (sCT) has long been used to treat bone disorders taking advantage of its essentially irreversible * This work was supported by National Institutes of Health Grant binding to the human receptor (15) and the ability of exogenous CT to affect bone turnover (16). Amy controls plasma glucose levels via AMY receptor activation that causes slowed gastric emptying, inhibition of glucagon secretion, and reduction of food intake (17). The Amy analog pramlintide is available for types I and II diabetes, and AMY receptor activation is under consideration as an obesity treatment (17,18).…”

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confidence: 99%

“…Amy controls plasma glucose levels via AMY receptor activation that causes slowed gastric emptying, inhibition of glucagon secretion, and reduction of food intake (17). The Amy analog pramlintide is available for types I and II diabetes, and AMY receptor activation is under consideration as an obesity treatment (17,18). Recently, amylin-mediated metabolic alteration was shown to induce regression of p53-deficient tumors (19).…”

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confidence: 99%

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Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Lee

Hay

Pioszak

2016

Journal of Biological Chemistry

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Receptor activity-modifying proteins (RAMP1-3) determine the selectivity of the class B G protein-coupled calcitonin receptor (CTR) and the CTR-like receptor (CLR) for calcitonin (CT), amylin (Amy), calcitonin gene-related peptide (CGRP), and adrenomedullin (AM) peptides. RAMP1/2 alter CLR selectivity for CGRP/AM in part by RAMP1 Trp-84 or RAMP2 Glu-101 contacting the distinct CGRP/AM C-terminal residues. It is unclear whether RAMPs use a similar mechanism to modulate CTR affinity for CT and Amy, analogs of which are therapeutics for bone disorders and diabetes, respectively. Here, we reproduced the peptide selectivity of intact CTR, AMY 1 (CTR⅐ RAMP1), and AMY 2 (CTR⅐RAMP2) receptors using purified CTR extracellular domain (ECD) and tethered RAMP1-and RAMP2-CTR ECD fusion proteins and antagonist peptides. All three proteins bound salmon calcitonin (sCT). Tethering RAMPs to CTR enhanced binding of rAmy, CGRP, and the AMY antagonist AC413. Peptide alanine-scanning mutagenesis and modeling of receptor-bound sCT and AC413 supported a shared non-helical CGRP-like conformation for their TN(T/ V)G motif prior to the C terminus. After this motif, the peptides diverged; the sCT C-terminal Pro was crucial for receptor binding, whereas the AC413/rAmy C-terminal Tyr had little or no influence on binding. Accordingly, mutant RAMP1 W84A-and RAMP2 E101A-CTR ECD retained AC413/rAmy binding. ECD binding and cell-based signaling assays with antagonist sCT/ AC413/rAmy variants with C-terminal residue swaps indicated that the C-terminal sCT/rAmy residue identity affects affinity more than selectivity. rAmy(8 -37) Y37P exhibited enhanced antagonism of AMY 1 while retaining selectivity. These results reveal unexpected differences in how RAMPs determine CTR and CLR peptide selectivity and support the hypothesis that RAMPs allosterically modulate CTR peptide affinity.Receptor activity-modifying proteins are single-pass transmembrane proteins (RAMP1-3 in humans) that form heteromeric complexes with several G protein-coupled receptors (GPCRs) 2 and thereby regulate their cell-surface expression and pharmacology (1, 2). RAMPs are best characterized for their effects on two class B GPCRs, the calcitonin receptor (CTR) and CTR-like receptor (CLR) (3). CTR/CLR and their complexes with RAMPs give rise to at least seven pharmacologically distinct receptors (not including splice variants) in humans that exhibit unique selectivity profiles for six related calcitonin (CT) family peptide agonists as follows: CT, amylin (Amy), calcitonin gene-related peptides ␣ and ␤ (␣CGRP and ␤CGRP), adrenomedullin (AM), and adrenomedullin2/intermedin (AM2) (2-4). CLR⅐RAMP1 is the CGRP receptor at which CGRP has greater potency than AM. CLR⅐RAMP2 and CLR⅐RAMP3 are the AM 1 and AM 2 receptors, respectively, at which AM is more potent than CGRP (1). AM2 activates the CGRP and AM receptors, but is most potent at AM 2 (5). CTR alone is the CT receptor at which CT is more potent than Amy. CTR complexes with RAMP1, -2, or -3 form distinct AMY 1 , AMY 2 , and AMY 3 rec...

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confidence: 99%

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confidence: 99%

Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Lee

Hay

Pioszak

2016

Journal of Biological Chemistry

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“…It acts at receptors in the area postrema of the brainstem to cause hypophagia, in part mediated by noradrenergic neurons. It also delays gastric emptying, resulting in decreased meal size and caloric intake [69,70,71]. Similar to GLP-1, it also inhibits post-prandial glucagon secretion, which contributes to hyperglycemia [72].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Prevention of type 2 Diabetes Mellitus: Potential of pharmacological agents

Samson

Garber

2016

Best Practice & Research Clinical Endocrinology & Metab

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“…Amylin is a 37-amino acid hormone, co-secreted with insulin in the pancreatic β-cells (Westermark, Andersson, & Westermark 2011), and its physiological role includes insulin secretion inhibition, inhibition of gastric emptying and glucagon secretion (Hay et al 2015). Endogenous amylin and its analogue and receptor agonist, salmon calcitonin (sCT), exert anorexigenic properties by signalling satiation (Lutz et al 1995;Lutz et al 2000;Reidelberger et al 2004;Mack et al 2007;Lutz 2012).…”

Section: Introductionmentioning

confidence: 99%

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

2018

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Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut-brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol-related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol-induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward-dependent memory consolidation. In addition, sCT pre-treatment attenuated alcohol intake in low alcohol-consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans.

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Amylin: Pharmacology, Physiology, and Clinical Potential

Cited by 289 publications

References 296 publications

Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Prevention of type 2 Diabetes Mellitus: Potential of pharmacological agents

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

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