Receptor Pharmacology

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Publisher Summary

Despite a clear evidence for a distinct amylin pharmacology and the 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. 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. The newly designated amylinomimetic drug class has been 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 an agonist 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.

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Summary

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

Molecular and Biochemical Characterization

The path leading to the molecular identity of the amylin receptor was circuitous. Before its characterization, several studies had suggested a close relationship between the amylin receptor and products of the calcitonin receptor gene. High‐affinity amylin binding sites were reported in MCF‐7 human breast carcinoma cells (Chen 1997, Zimmermann 1997). Expression cloning experiments using a peptide antagonist of amylin and calcitonin receptors identified two isoforms of the calcitonin receptor

Brain Distribution

The distribution of sites corresponding to amylin receptors was first identified by Sexton et al. in 1988 (Sexton et al., 1988). They were first termed C3 binding sites, characterized as calcitonin binding sites that also had high affinity to both sCT and CGRP (Sexton et al., 1988). But, since amylin had just been discovered, these authors did not recognize that the C3 sites also bound amylin with high affinity. The discovery that these sites contained amylin receptors was made by Beaumont in

Definition of Amylinomimetic Class

Before molecular characterization of amylin receptors, pharmacological and anatomic characterization of an amylin receptor class was apparent, with selective ligands showing distinctive patterns of activities in bioassays, affinities in binding studies, and distributions of selective binding. These distinctions allowed for a definition of an amylinomimetic class of ligands.

Binding potencies at membranes from the nucleus accumbens in rat (Beaumont et al., 1993) indicated a unique pharmacology

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      Our in vitro study showed that human amylin with a concentration from 10 ng/ml (∼2.5 nM) to 10 μg/ml (∼2.5 μM) was beneficial to antagonize the neurotoxicity caused by aggregated Aβ1-42 in rat cortical neurons. The average fasting plasma amylin concentrations are in the range of 4–25 pmol/l in healthy humans (Nyholm et al., 1998), the peak of amylin in the amylin treatment we conducted for the mice was ∼1 nmol/l and the half-life of exogenous amylin or pramlintide is about 20–45 min in vivo (Colburn et al., 1996; Young, 2005b). Since MCI and AD patients have lower concentrations of plasma amylin than healthy controls (Adler et al., 2014; Zhu et al., 2015), the potential benefits of amylin-type peptides with a physiological concentration as a neuropeptide should not be ignored.

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      Hence, we used AMY receptor antagonists rAMY8-37, AC187 and CGRP8-37 to characterize the nature of receptors that mediate inhibitory effects of AMY on the formalin-induced hyperalgesia. AC187 is generally accepted as a good discriminator of amylinergic responses (Young, 2005). rAMY8-37 is also generally accepted as a selective but weak antagonist at AMY receptors with an affinity profile of AMY1 > AMY3 ⋙ rCT (Hay et al., 2005).

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      The CTR can be activated by several closely related peptides including calcitonin, amylin, adrenomedullin, and CGRP. The CTR alone has the highest affinity for calcitonin [25,26], but enhanced selectivity for amylin binding is conferred by association with a RAMP [27,28], of which there are three possible subtypes for the amylin receptor complex (RAMP1, RAMP2, RAMP3) [29]. Together with the two splice variants of CTR, this totals six unique CTR/RAMP combinations that can form a functional amylin receptor [30], although RAMP1 and RAMP3 may confer greater amylin binding selectivity than RAMP2 [27,28].

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