Selective amylin antagonist suppresses rise in plasma lactate after intravenous glucose in the rat

Young, Andrew; Gedulin, Bronislava; Gaeta, Laura S.L.; Prickett, K S; Beaumont, Kevin; Larson, Erica L.; Rink, T J

doi:10.1016/0014-5793(94)80563-6

Cited by 44 publications

(20 citation statements)

References 27 publications

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“…N-terminally truncated antagonist fragments of sCT, human calcitonin (hCT), rAmy, h␣CGRP, and human AM were used as competitors. Binding of AMY receptor antagonist peptides AC413 and AC187 (42) and an antagonist fragment (residues 8 -37) of the diabetes drug pramlintide (43) were also evaluated. Hereafter, we refer to the recombinant fusion proteins without the use of "MBP" for simplicity.…”

Section: Calcitonin Family Peptide Binding Profiles Of Purified Ctr Ementioning

confidence: 99%

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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Section: Calcitonin Family Peptide Binding Profiles Of Purified Ctr Ementioning

confidence: 99%

Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Lee

Hay

Pioszak

2016

Journal of Biological Chemistry

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“…According to animal studies, IAPP may play a role for insulin resistance in rats (13)(14)(15) and dogs (16), while its importance for glucose metabolism in humans is currently being investigated. Islet amyloid polypeptide has been proposed to be a pathogenic factor in noninsulin-dependent diabetes mellitus (17) and an inverse correlation has been reported between the IAPP/insulin ratio and glucose disposal in obese man (18), while in another study, no correlation could be found between an insulin sensitivity index and IAPP release (19).…”

Section: Discussionmentioning

confidence: 99%

Increased plasma levels of islet amyloid polypeptide in patients with primary hyperparathyroidism

Valdemarsson¹,

Leckström

Westermark

et al. 1996

European Journal of Endocrinology

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Amylin, also named islet amyloid polypeptide (IAPP), is a protein that is processed and released from pancreatic beta-cells in parallel with insulin. Islet amyloid polypeptide is currently studied with regard to a role for insulin resistance in non-insulin-dependent diabetes. To elucidate a possible function of IAPP for impaired glucose tolerance in primary hyperparathyroidism (pHPT), we studied plasma IAPP levels during an oral glucose tolerance test (OGTT) in seven pHPT patients before and 8 weeks after surgery and in six healthy subjects. The B-glucose level of the patient groups was 4.34 +/- 0.12 mmol/l before and 3.97 +/- 0.16 mmol/l after surgery (NS), while the serum level of insulin was significantly higher before (16.9 +/- 2.8 mlU/l) than after (8.9 +/- 1.9 mlU/l) the operation (p < 0.05), indicating a moderately increased insulin resistance in pHPT. The basal plasma levels of IAPP were significantly higher in pHPT patients before than 8 weeks after surgery (9.71 +/- 1.05 and 4.30 +/- 0.82 pmol/l, respectively: p < 0.01). When compared to the plasma IAPP level of the controls at 1.80 +/- 0.38 pmol/l, pHPT patients had higher IAPP values both before (p < 0.01) and at 8 weeks after (p < 0.05) operation. There was a significant correlation between the serum levels of insulin and plasma levels of IAPP in pHPT patients before (r = 0.87, p < 0.01) as well as 8 weeks after surgery (r = 0.69, p < 0.05). The area under the curve for IAPP during OGTT in pHPT patients was 1872.4 +/- 187.7 pmol.min/l, which is significantly higher than after surgery (1010.8 +/- 93.7 pmol.min/l) (p<0.05) and compared to the area for the controls at 840.3 +/- 49.9 pmol.min/l (p<0.01). In conclusion, pHPT is associated with an increased plasma level of IAPP, correlated to the serum insulin level, but persistently higher than in controls also 8 weeks after surgery. Possibly, increased IAPP levels can have a role for impaired glucose tolerance in pHPT. The hyperparathyroid state might have a specific role for the release of this peptide, otherwise closely connected to insulin secretion

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“…Human amylin and AC 187, an amylin receptor antagonist (AcVal-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-TyrPro-Arg-Thr-Asn-Thr-Gly-Ser-Asn-Thr-Tyr-NH 2 ) (Young et al 1994), were obtained from SynPep (Dublin, CA), A␤ 25-35 from QCB Biosource International (Camarillo, CA), and iberiotoxin from Sigma Chemical (St. Louis, MO). All the agents were dissolved in distilled water to make 1,000ϫ stock solution (stored at Ϫ70°C) and diluted in external perfusing medium just before the time of application.…”

Section: Drugs and Solutionsmentioning

confidence: 99%

Human Amylin Actions on Rat Cholinergic Basal Forebrain Neurons: Antagonism of Beta-Amyloid Effects

Jhamandas

Harris

Cho

et al. 2003

Journal of Neurophysiology

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. Human amylin (hAmylin), a 37-amino acid pancreatic peptide, and amyloid ␤ protein (A␤), a 39 -43 amino acid peptide, abundantly deposited in the brains of Alzheimer's patients, induce neurotoxicity in hippocampal and cortical cultures. Although the mechanism of this neurotoxicity is unknown, both peptides are capable of modulating ion channel function that may result in a disruption of cellular homeostasis. In this study, we examined the effects of hAmylin on whole cell currents in chemically identified neurons from the rat basal forebrain and the interactions of hAmylininduced responses with those of A␤. Whole cell patch-clamp recordings were performed on enzymatically dissociated neurons of the diagonal band of Broca (DBB), a cholinergic basal forebrain nucleus. Bath application of hAmylin (1 nM to 5 M) resulted in a dosedependent reduction in whole cell currents in a voltage range between Ϫ30 and ϩ30 mV. Single-cell RT-PCR analysis reveal that all DBB neurons responding to hAmylin or A␤ were cholinergic. Using specific ion channel blockers, we identified hAmylin and A␤ effects on whole cell currents to be mediated, in part, by calcium-dependent conductances. Human amylin also depressed the transient outward (I A ) and the delayed rectifier (I K ) potassium currents. The hAmylin effects on whole cell currents could be occluded by A␤ and vice versa. Human amylin and A␤ responses could be blocked with AC187 (50 nM to 1⌴), a specific antagonist for the amylin receptor. The present study indicates that hAmylin, like A␤, is capable of modulating ion channel function in cholinergic basal forebrain neurons. Furthermore, the two peptides may share a common mechanism of action. The ability of an amylin antagonist to block the responses evoked by hAmylin and A␤ may provide a novel therapeutic approach for Alzheimer's disease. I N T R O D U C T I O NAlzheimer's disease (AD), the most prevalent form of dementia, is a progressive neurodegenerative disease characterized by the loss of memory and higher cognitive functions (Selkoe 2001). The neuropathological features associated with AD include the presence of extracellular neuritic plaques composed of amyloid ␤ protein (A␤), intracellular neurofibrillary tangles, and the loss of basal forebrain cholinergic neurons that innervate the hippocampus and the cortex (Price 1986; Selkoe 1999). The principal constituents of the amyloid deposits is A␤, which is a 39 -43 amino acid peptide generated by proteolytic cleavage of a larger amyloid precursor protein. The in vitro neurotoxic potential of A␤ peptides when applied to either primary rat or human neuronal cultures has been advanced in the "amyloid hypothesis" to explain a central role for A␤ in neuronal death in AD (Kar et al. 1996;Mattson et al. 1992).Human amylin (hAmylin) is a 37-amino acid peptide that is a major constituent of protein deposits identified in the islets of Langerhans of patients with noninsulin-dependent diabetes mellitus. Despite limited primary sequence homology, hAmylin shares several biophysical propert...

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Selective amylin antagonist suppresses rise in plasma lactate after intravenous glucose in the rat

Cited by 44 publications

References 27 publications

Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Calcitonin and Amylin Receptor Peptide Interaction Mechanisms

Increased plasma levels of islet amyloid polypeptide in patients with primary hyperparathyroidism

Human Amylin Actions on Rat Cholinergic Basal Forebrain Neurons: Antagonism of Beta-Amyloid Effects

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