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Understanding Amylin Receptors

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The calcitonin gene-related peptide family

Abstract

Amylin is a 37 amino acid peptide that is co-secreted with insulin from pancreatic β-cells following nutrient ingestion, acting to inhibit gastric emptying, feeding and insulin-stimulated glycogen synthesis. Amylin is a member of the calcitonin (CT) family of peptides, which include CT, CT gene-related peptides (CGRP) and adrenomedullin (AM). The receptors for these peptides comprise the CT receptor (CTR) and the CTR-like receptor (CLR) that may be complexed with one of three receptor activity modifying proteins (RAMPs). Amylin receptors are formed when the CTR is in complex with RAMP1, RAMP2 or RAMP3, forming AMY1, AMY2 and AMY3 receptors, respectively. Each of these receptors, while binding amylin with similar affinity, has a distinct agonist and antagonist pharmacology. Analysis of RAMP chimeras and deletion constructs has provided insight into domains of RAMPs that contribute to ligand and signaling specificity. The N-terminal domain is the principle domain involved in alteration of ligand binding specificity, while the C-terminal domain contributes to the peptide signaling profile of the receptor complexes and could be directly involved in the interaction with G proteins.

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Abbreviations

AC:

adenylyl cyclase

AM:

adrenomedullin

AMY:

amylin receptor

AM2:

adrenomedullin 2

cAMP:

cyclic adenosine monophosphate

cDNA:

complementary DNA

CGRP:

calcitonin gene-related peptide

CHO:

chinese hamster ovary cells

CLR:

calcitonin receptor-like receptor

CNS:

central nervous system

COS:

african green monkey kidney cells

CT:

calcitonin

CTR:

calcitonin receptor

CT(a) :

calcitonin receptor a isoform

CT(b) :

calcitonin receptor b isoform

ERK:

extracellular signal-regulated protein kinase

GPCR:

G protein-coupled receptor

HEK293:

human embryonic kidney cells

IDDM:

insulin dependent diabetes mellitus or type 1 diabetes

IMD:

intermedin, also known as AM2

IP:

inositol phosphate

IP3 :

inositol 1,4,5-trisphosphate

MDCK:

mandin-darby canine kidney cells

NHERF1:

Na+/H+ exchanger regulatory factor 1

NIDDM:

non IDDM or type 2 diabetes

NSF:

N-ethylmaleimide-sensitive fusion protein

PDZ:

post-synaptic density-95/discs large/Zone occludens-1 homology

PKA:

protein kinase A

PLC:

phospholipase C

RAEC:

rabbit aortic endothelial cells

RAMP:

receptor activity modifying protein

RCP:

receptor component protein

Δ:

deletion mutant.

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Authors and Affiliations

  1. Zealand Pharma, Smedeland 26B, DK-2600, Glostrup, Denmark

    Rasmus Just

  2. Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences and Department Pharmacology, Monash University, Victoria, Australia

    John Simms, Sebastian G. B. Furness, Arthur Christopoulos & Patrick M. Sexton

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  1. Rasmus Just
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  2. John Simms
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  3. Sebastian G. B. Furness
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  4. Arthur Christopoulos
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  5. Patrick M. Sexton
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Correspondence to Rasmus Just .

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Editors and Affiliations

  1. School of Biological Sciences, University of Auckland, Symonds St. 9, Auckland , 1142, New Zealand

    Deborah L. Hay

  2. University of Auckland, Symonds Street 3A, Auckland, 1142, New Zealand

    Ian M. Dickerson

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Just, R., Simms, J., Furness, S.G.B., Christopoulos, A., Sexton, P.M. (2010). Understanding Amylin Receptors. In: Hay, D., Dickerson, I. (eds) The calcitonin gene-related peptide family. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2909-6_3

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