ReviewReceptor autoradiography as mean to explore the possible functional relevance of neuropeptides: focus on new agonists and antagonists to study natriuretic peptides, neuropeptide Y and calcitonin gene-related peptides☆
Introduction
Early on, receptor autoradiography proven most useful as a mean to explore the possible pathophysiological relevance of various family of peptides in the central and peripheral nervous systems (for review [46]). We were first to report on the discrete distribution of neuropeptide Y (NPY) receptor binding sites in the rat brain in Peptides in 1986 [250]. It was also in Peptides that we were first to demonstrate the discrete distribution of specific atria natriuretic peptide (ANP) binding sites in the rat brain [308]. These data were highly suggestive of the existence of brain peptides related to the ANP family. This hypothesis was subsequently confirmed with the isolation of brain natriuretic peptides (BNPs) [360]. Finally, data on the discrete localization of calcitonin gene-related peptide (CGRP) receptors in the brain were first reported in PNAS [377] and demonstrated that CGRP receptors were distinct from calcitonin (CT) receptors. This review will summarize recent findings about these three families of peptides.
The natriuretic peptide family is composed of three peptides namely ANP, BNP and C-type natriuretic peptides (CNPs) [330]. ANP was the first member of this peptide family to be isolated from the atria [77]. Two other natriuretic peptides, BNP and CNP, were isolated from porcine brain [360], [362]. Although BNP was first isolated from porcine brain, it was later found to be predominantly produced by the heart and vascular endothelial cells [285]. These peptides share a common core structure (a 17 amino acids disulfide ring) which is essential for their biological actions. Most research on these peptides has focused on their peripheral effects in the heart, blood vessels and kidney while much less is currently known about their role in the central nervous system [223], [330]. ANP, BNP and CNP bind to two single-transmembrane proteins which belong to a family of guanylyl cyclase (GC)-coupled receptors termed GC-A and GC-B [223], [266], [374]. They are also known as NPR-A or NPR-1 and NPR-B receptors [330]. Additionally, a third receptor designated as NPR-C is a clearance or silent receptor [125], [244]. The pharmacological and molecular profiles of each receptor subtype are summarized in Table 1.
The NPY family includes NPY and two other peptides known as peptide YY (PYY) and the pancreatic polypeptides (PPs) [367]. NPY is one of the most abundant peptide expressed in the mammalian brain [49], [50], [78], [79], while PYY and PPs are mostly found in endocrine cells of the intestinal tract [353]. It is now well established that NPY induced its effects via the activation of at least five receptor subtypes termed Y1, Y2, Y4, Y5 and y6 [261]. All these receptors have been cloned and belong to the type I GPCR receptor family [101]. Each NPY receptor subtype has distinctive pharmacological profile as defined using various agonists and antagonists. Most agonists can activate more than one receptor subtype while antagonists generally display higher selectivity (Table 2).
The calcitonin family includes CT, amylin (AMY), two CGRPs termed CGRPα and CGRPβ, adrenomedullin (AM) [301] and two most recently isolated peptides called calcitonin receptor-stimulating peptide (CRSP) [206] and intermedin [321]. Key features of this peptide family is the presence of a disulfide bridge in the N-terminus and the deletion of amino acid residues in this region generates C-terminal fragments [CGRP(8–37) and others] with antagonistic properties [81], [83]. The biological effects induced by this peptide family are mediated via binding to two closely related type II GPCRs, the calcitonin receptor (CTR) and calcitonin receptor-like receptor (CRLR). Moreover, and in contrast to most GPCRs, CTR and CRLR require the presence of chaperone proteins such as the receptor-activity-modifying-proteins (RAMPs) [254] and receptor-component-protein (RCP) [233] in order to provide functional responses to CGRP, AM and AMY. Furthermore, depending of the associated RAMPs distinctive pharmacological profiles can be generated [301]. These profiles are summarized in Table 3.
Section snippets
Natriuretic peptide family
Natriuretic peptides (NPs) are members of a family of vasoactive hormones that play important roles in the regulation of blood pressure, cardiovascular homeostasis and kidney functions [223], [330], [374]. ANP is a cardiac peptide derived from a 151 (rat) and 152 (human) amino acid residue preprohormone which by proteolytic cleavage (Ser99–Tyr126) results in an active peptide of 28 amino acids [ANP(1–28)] [77]. BNP is a 32 amino acid peptide that although first isolated from porcine brain has
The NPY family
NPY is a 36 amino acid residues polypeptide, first isolated from porcine brain [366]. This peptide shares not only high sequence homologies with PYY and the PPs but also structural elements which confer a hairpin-like structure to these molecules [4], [245]. NPY is one of most evolutionary conserved peptides [225], suggesting significant roles in basic physiological functions. In fact, this peptide family has demonstrated a broad range of biological effects including increased food and water
Calcitonin and calcitonin gene-related peptide family
The first peptide of this family was isolated from the thyroid gland and called CT. This peptide is implicated in calcium homeostasis and bone resorption [68]. Many years later, molecular cloning of DNA complementary to rat CT mRNA revealed that the CT gene could generate a second distinct transcript coding for a 37 amino acid polypeptide named CGRP [6], [324]. The possible existence of other gene products related to CGRP was investigated by screening library and resulted in the identification
General conclusion
The development of highly selective agonists and antagonists is critical in order to clearly establish the functional significance of a given receptor subtype. Without such tools it is very difficult to obtain definitive answers. Additionally, the development of radiolabeled molecules highly selective for a receptor subtype is important to precisely access discrete receptor distribution and to characterize receptor binding properties. Finally, receptor localization has clearly proven to be most
References (417)
- et al.
Distribution and molecular forms of brain natriuretic peptide in the central nervous system, heart and peripheral tissue of rat
Biochem. Biophys. Res. Commun.
(1989) - et al.
Receptor-selective analogs demonstrate NPY/PYY receptor heterogeneity in rat brain
Neurosci. Lett.
(1991) - et al.
Neuropeptide Y: role in light-dark cycle entrainment of hamster circadian rhythms
Neurosci. Lett.
(1984) - et al.
Characterization of the human type 2 neuropeptide Y receptor gene (NPY2R) and localization to the chromosome 4q region containing the type 1 neuropeptide Y receptor gene
Genomics
(1996) - et al.
Atrial natriuretic factor inhibits adenylate cyclase activity
Biochem. Biophys. Res. Commun.
(1984) - et al.
Ring-deleted analogs of atrial natriuretic factor inhibit adenylate cyclase/cAMP system. Possible coupling of clearance atrial natriuretic factor receptors to adenylate cyclase/cAMP signal transduction system
J. Biol. Chem.
(1990) - et al.
Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor
J. Pharmacol. Toxicol. Methods
(1999) - et al.
Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY
J. Biol. Chem.
(1995) - et al.
Expression of calcitonin gene-related peptide, substance P and protein kinase C in cultured dorsal root ganglion neurons following chronic exposure to mu, delta and kappa opiates
Neuroscience
(2002) - et al.
Activity of amylin at CGRP1-preferring receptors coupled to positive contractile response in rat ventricular cardiomyocytes
Regul. Pept.
(1995)
The cloned guinea pig neuropeptide Y receptor Y1 conforms to other mammalian Y1 receptors
Peptides
Effects of brain natriuretic peptide-32 on the extinction of active avoidance behavior in rats. Transmitter-mediated action
Physiol. Behav.
The effects of atrial natriuretic peptide on passive avoidance behaviour in rats
Brain Res. Bull.
Effect of receptor blockers on brain natriuretic peptide and C-type natriuretic peptide caused anxiolytic state in rats
Neuropeptides
GW1229, a novel neuropeptide Y Y1 receptor antagonist, inhibits the vasoconstrictor effect on neuropeptide Y in the hamster microcirculation
Eur. J. Pharmacol.
Molecular biology and pharmacology of multiple NPY Y5 receptor species homologs
Regul. Pept.
In vivo central actions of NPY(1–30), an N-terminal fragment of neuropeptide Y
Peptides
Distribution of a novel hypothalamic neuropeptide Y receptor gene and it’s absence in rat
Mol. Brain Res.
The first selective agonist for the neuropeptide Y Y5 receptor increases food intake in rats
J. Biol. Chem.
Y-receptor affinity modulation by the design of pancreatic polypeptide/neuropeptide Y chimera led to Y5-receptor ligands with picomolar affinity
Peptides
Anorexia following the intrahypothalamic administration of amylin
Brain Res.
Effects of neuropeptide Y on the electrical properties of neurons
Trends Neurosci.
Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist
Regul. Pept.
A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats
Life Sci.
Distribution of neuropeptide Y-like immunoreactivity in the rat central nervous system—I. Radioimmunoassay and chromatographic characterisation
Neuroscience
Distribution of neuropeptide Y-like immunoreactivity in the rat central nervous system—II. Immunohistochemical analysis
Neuroscience
Calcitonin gene-related peptide (hCGRP alpha) binding sites in the nucleus accumbens. Atypical structural requirements and marked phylogenic differences
Brain Res.
BIIE0246: a selective and high affinity neuropeptide Y Y2 receptor antagonist
Eur. J. Pharmacol.
Differential distribution of neuropeptide Y1 and Y2 receptors in the rat brain
Eur. J. Pharmacol.
Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues
Prog. Neurobiol.
Molecular structure of mammalian neuropeptide Y: analysis by molecular cloning and computer-aided comparison with crystal structure of avian homologue
Proc. Natl. Acad. Sci. U.S.A.
Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide
Science
Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products
Nature
Atrial natriuretic factor inhibits dehydration- and angiotensin II-induced water intake in the conscious, unrestrained rat
Proc. Natl. Acad. Sci. U.S.A.
Central administration of atrial natriuretic factor inhibits saline preference in the rat
Endocrinology
Effects of adrenomedullin, calcitonin gene-related peptide, and amylin on cerebral circulation in dogs
J. Cereb. Blood Flow Metab.
High affinity amylin binding sites in rat brain
Mol. Pharmacol.
Differential antagonism of amylin’s metabolic and vascular actions with amylin receptor antagonists
Can. J. Physiol. Pharmacol.
Regulation of muscle glycogen metabolism by CGRP and amylin: CGRP receptors not involved
Br. J. Pharmacol.
A novel cyclic analog of neuropeptide Y specific for the Y2 receptor
Eur. J. Biochem.
Structure/activity relationships of C-terminal neuropeptide Y peptide segments and analogues composed of sequence 1–4 linked to 25–36
Eur. J. Biochem.
Adrenomedullin and calcitonin gene-related peptide (CGRP) interact with a common receptor of the CGRP1 subtype in the human adrenal zona glomerulosa
Endocr. Res.
Rat adrenomedullin induces a selective arterial vasodilation via CGRP1 receptors in the double-perfused mesenteric bed of the rat
Can. J. Physiol. Pharmacol.
Islet amyloid polypeptide—hen or egg in type 2 diabetes pathogenesis?
Acta Oncol.
Discovery and optimization of a series of carbazole ureas as NPY5 antagonists for the treatment of obesity
J. Med. Chem.
Receptors for calcitonin gene-related peptide, adrenomedullin, and amylin: the contributions of novel receptor-activity-modifying proteins
Receptors Channels
Functional interaction of G protein-coupled receptors of the adrenomedullin peptide family with accessory receptor-activity-modifying proteins (RAMP)
Microsc. Res. Tech.
The demonstration of vasodilator activity of pancreatic amylin amide in the rabbit
Am. J. Pathol.
Diverse biological actions of atrial natriuretic peptide
Physiol. Rev.
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DOI of original article: 10.1016/0196-9781(84)90183-9.