Neuropeptide Y receptors: Introduction


Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are closely related polypeptides based on structural and evolutionary criteria [8,42]. They consist of 36 amino acids (aa) each and share considerable amino acid identity, amidated C-termini and the presence of a large number of tyrosine (abbreviated by the letter Y in the single letter amino acid code) residues including both ends of the molecule (with a few exceptions), hence the name [42]. These peptides also have a characteristic tertiary structure, which has been termed the 'PP-fold' based on crystallography of turkey PP [42]. The PP-fold is U-shaped and consists of an extended polyproline helix and an α-helix connected by a β turn. Endogenously occurring long C-terminal fragments of NPY and PYY, i.e. NPY3-36 and PYY3-36 have been described [23,30]. These are not mere degradation products but are actively formed by the enzyme dipeptidyl peptidase IV (also known as CD26) [54], and the occurrence of PYY3-36 in plasma appears to be regulated by mechanisms that may be distinct from those regulating release of PYY, since physiological stimuli such as food intake may differentially alter the plasma levels of both peptides in man [29].

Endogenous peptides

NPY, PYY and PP can usually be distinguished based on their amino acid sequences [42]. NPY in mammals is primarily synthesised and released by neurones, which in the peripheral nervous system are predominantly sympathetic neurones. PYY is predominantly synthesised and released by intestinal endocrine cells, and can also coexist with glucagon in pancreatic acini and enteroglucagon in endocrine cells of the lower bowel. PP is mainly found in pancreatic cells distinct from those storing insulin, glucagon or somatostatin. However, in some cases other cell types can also express NPY, PYY and PP. While NPY acts as a neurotransmitter, PYY and PP in mammals act as hormones.

Physiological effects attributed to NPY include stimulation of food intake [3,12,44,67], inhibition of anxiety in the CNS [13,35,71], presynaptic inhibition of neurotransmitter release in the CNS and periphery [47], modulation of circadian rhythm [53,74-75], release of pituitary hormones [52,62], modulation of hippocampal activity [14,24,40], pain transmission [9,37], vasoconstriction [48,57], inhibition of insulin release [65,68,70] and modulation of renal function [6,55].

Physiological effects attributed to PYY include slowing of intestinal transit [11,46], inhibition of gastrointestinal anion and electrolyte secretion [15] and appetite inhibition [1,16]. Physiological effects attributed to PP include appetite stimulation [2,41].

While PP was discovered first and NPY last, evolutionary analysis shows that PP actually is the newest member of the family [42]. Both NPY and PYY are found in representatives of all major vertebrate groups. NPY is the most highly conserved; even the sequence in Torpedo marmorata is identical to mammalian NPY in 33 out of 36 positions. PYY and NPY presumably evolved by duplication from a common ancestral gene in an early vertebrate ancestor. These genes are located on different chromosomes. The PP gene arose in a tetrapod ancestor by duplication of the PYY gene; these genes are located close to one another in the same chromosomal segment [42]. Based on these evolutionary considerations, it is recommended that the family is termed the 'NPY family'.

Receptor classification and nomenclature

The members of the NPY family act upon the same family of receptors. Therefore, it is recommended that the receptors for NPY, PYY and PP are classified together as 'NPY receptors' [56]. The NPY receptors are designated by an upper case Y, corresponding to the use in the tyrosine-rich peptide names. The various NPY receptors within the family are designated by subscript numbers, e.g. Y1, Y2 etc. While non-mammalian NPY receptor types have been identified that are distinct from all those described below, they are not included in this classification.

At present five distinct NPY receptors have been established by receptor cloning studies. With regard to endogenous agonists, the receptors Y1, Y2 and Y5 preferentially bind NPY and PYY, whereas the Y4 receptor preferentially binds PP; relative to Y1 and Y4 receptors, the Y2 and Y5 receptors are also potently activated by NPY3-36 and PYY3-36 [27]. The pharmacological profile of the y6 receptor is controversial; since this 'receptor' is non-functional in primates including humans [31,50] and absent from the rat genome [10], little information has been published following its initial identification.

With regard to synthetic NPY analogues and fragments, the pharmacological profiles of the Y1 and Y2 receptors have been clearly established, but those of the Y4, Y5 and y6 receptors require a more extensive investigation, especially with regard to the endogenously expressed receptors. Several NPY responses with a Y5 receptor-like pharmacological profile have been described in peripheral tissues, but Y5 receptor mRNA expression is largely restricted to the CNS [7]. The family of NPY receptors can be sorted into three subfamilies [43]: the Y1 subfamily consisting of subtypes Y1, Y4, Y6 and Y8 (the latter found in frogs and fishes); the Y2 subfamily consisting of subtypes Y2 and Y7 (the latter found in non-mammalian jawed vertebrates); and the Y5 subtype remaining alone in a seperate subfamily. All seven of these receptors arose in the vertebrate ancestor whereupon some subtypes were lost in some evolutionary lineages.

Additional sites

It has been reported that PYY is considerably less active than NPY in several model systems including rat CNS [32], rat and bovine adrenals [4,61] and in the adrenal-derived PC12 cell line [51]. This site of action of NPY has been referred to as a 'Y3 receptor'. However, at present the evidence for the existence of a distinct Y3 site is circumstantial only, because the receptor has not been cloned and no specific agonists or antagonists have been described. An early report on the cloning of a rat NPY receptor with greater potency for NPY than for PYY [64] was later shown to result from an artefact [36,38]. Therefore, the present evidence is not sufficient to grant the proposed Y3 site status as a receptor. Since this designation has already been used by various investigators, it is suggested that the third place in the NPY receptor classification is left vacant for the time being and that binding sites and responses where NPY is considerably (at least 10-fold) more potent than PYY are referred to as 'putative Y3 receptors'.

Several reports have used the term 'PYY-preferring receptor' [33]. In most cases it has been applied to describe a receptor where PYY was three- to five-times more potent than NPY. However, a PYY preference of this small magnitude is observed for many Y1 receptor-mediated responses and may be a general feature of this receptor rather than the hallmark of an additional type. Thus, convincing evidence for the existence of such a new receptor is lacking.

NPY and related peptides can induce histamine release from mast cells, but it is questionable whether this is a receptor-mediated event [60].

Signal transduction

All NPY receptors couple to pertussis toxin-sensitive G proteins of the Gi or Go family (inhibition of adenylate cyclase) [56]. Additional signalling responses have been reported but appear to be restricted to certain cell types. These include inhibition of Ca2+ channels, e.g. in neurones [25], and activation and inhibition of K+ channels, e.g. in cardiomyocytes [58] and vascular smooth muscle cells [73], respectively. Based on experiments with Ca2+ entry blockers, it has been postulated that NPY stimulates Ca2+ channels in the vasculature [57]. In some cell types members of the NPY family can mobilise Ca2+ from intracellular stores; while this appears to involve inositol phosphates in some cells [63], inositol phosphate-independent Ca2+ mobilisation has been postulated in other cell types [59]. A sensitivity of certain NPY responses to the cyclooxygenase inhibitor, indomethacin, indicates possible coupling of NPY receptors to a phospholipase A2 [5,49], but this has yet to be definitively demonstrated. Activation of a phospholipase D or of a tyrosine kinase, which can occur with some Gi/Go protein-coupled receptors has also not clearly been demonstrated to date, but activation of mitogen-activated protein kinases can occur [39]. Thus, the coupling of NPY receptors to the Gi or Go protein family, is followed by the responses typically under the control of these G proteins [45]. However, it should be noted that studies with endogenously expressed receptors have mainly been performed with Y1 receptors (and to a lesser extent with Y2 receptors), whereas investigations of the signal transduction of other natively expressed NPY receptors are largely missing. Reference [55] outlines the signalling of the NPY receptors.

Pharmacological tools for NPY receptor classification

Historically the subdivision of NPY receptors comes from the observation that C-terminal fragments of NPY or PYY, e.g. NPY13-36, can mimic some NPY responses, e.g. prejunctional inhibition of twitch responses in the rat vas deferens, but not others, e.g. vasoconstriction in guinea-pig iliac vein [69]. Based on these findings it was proposed that receptors that are only activated by the holopeptides are designated Y1, while those that are activated by the holopeptides and the C-terminal fragment are designated Y2. While numerous C-terminal fragments have been synthesised, the 3-36, 13-36 and 18-36 fragments of NPY and PYY are most frequently used without apparent advantages between them. C-terminal NPY fragments are still useful to discriminate Y1 and Y2 receptors, but they are not selective for Y2 receptors since they can also activate Y5 receptors at similar concentrations [27]. In contrast to NPY and PYY, PP contains a Pro in position 34 of the molecule. [Pro34]-substituted forms of NPY or PYY, i.e. [Leu31, Pro34]NPY [61] or [Pro34]PYY are selective for Y1 relative to Y2 receptors. An additional [Leu31]-substitution in [Pro34]-substituted analogues does not appear to be important for Y1 selectivity [26,28]. More recent data, however, show that [Pro34]-substituted NPY and PYY analogues also potently activate Y5 receptors [27].

NPY, PYY, C-terminal fragments and [Pro34]-substituted analogues thereof, and PP are still important tools with which to characterize NPY receptors, particularly since they are commercially available. However, the classification of receptors based on agonists is notoriously unreliable. Moreover, it should be noted, that in some cases the species of origin of the agonist may be important for its potency, and this is particularly true of species variants of PP. Apart from NPY antisera [18], non-selective NPY antagonists have not been described. However, several selective NPY receptor antagonists have now been described. The first small molecule NPY receptor antagonist was BIBP3226, which is selective for Y1 receptors relative to all other types and for which an inactive stereoisomer is available as a control [21]. A successor of BIBP3226 with similar selectivity but improved potency is BIBO3304 [72]. GR231118 (also known as GW1229 or 1229U91) is another Y1 receptor-selective antagonist [19,34] but its use is complicated by the fact that it is also a Y4 agonist [66]. BIIE0246 is a selective Y2 receptor antagonist [20,22], and CGP71683A is a selective Y5 receptor antagonist [17]. Several other compounds have been reported to be selective antagonists, but these reports either await confirmation by other laboratories and/or these compounds have not been made freely available to investigators. Overall it should be borne in mind that most of the available tools are not fully selective and that significant differences in receptor affinities for their cognate ligands exist between species. Receptor identification therefore, has to rely on the use of a combination of complementary agents. This caveat applies even more significantly in vivo, where compounds are less characterized than in vitro.


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