Prolactin-releasing peptide receptor: Introduction

The Prolactin-releasing Peptide receptor

The Prolactin-Releasing Peptide receptor (PrRP receptor) is a member of the rhodopsin family of GPCRs [19] which was originally identified as the orphan receptor GPR10 [37]. PRRP is also known as the prolactin releasing hormone receptor (PRLHR) according to HUGO Gene Nomenclature Committee. The PrRP receptor contains an extracellular domain with two disulphide bridges for ligand binding, a duplicated tryptophan–serine (WS) motif, as well as a single transmembrane domain and an intracellular signal-transducing domain [5,8]. The receptor is expressed in several parts of the brain and most notably in the reticular thalamic nucleus, the periventricular (PerVN), paraventricular (PVN) and the dorsomedial hypothalamus (DMH), the nucleus of the solitary tract (NTS) and the anterior pituitary [47].

The Prolactin-releasing Peptide

The PrRP receptor binds two endogenous ligands, the 20 and the 31 amino acid long prolactin-releasing peptide (PrRP-20 and PrRP-31), where the 20 amino acid long peptide is the truncated version of the longer one [26,52]. PrRP is predominately expressed in cell bodies in the dorsomedial hypothalamus, the NTS and the ventrolateral reticular nucleus of the rat brain [38,47].


The PrRP receptor was reported to stimulate prolactin release from rat pituitary cells, hence the name [20,26] . A direct prolactin-releasing effect of PrRP in mammals has however been questioned because no PrRP immunoreactive fibres were observed in the median eminence where classical hypophysiotropic hormones are released [38]. This, together with the discovery that prolactin positive cells in the human pituitary do not co-localise with the PRRP receptor [1] and the findings that PrRP does not significantly increase prolactin secretion [13,51], has suggested that PrRP is associated with other neuroendocrine functions.

PrRP receptor activity has a well-known implication in hypogonadotropic hypogonadism and anovulatory infertility [43,49], although mechanisms underlying pathophysiology remain unclear [5]. Similarly, conflicting results are reported in the initiation and/or progression of some type of cancers due to impairments in prolactin signalling [3,5,10,48,53]. Genetic variants of PrRP receptor were associated with breast cancer [7,12,41,54] although some inconsistencies are reported [35,44]. The other hand, blockade of PRLR signalling pathway in human tumors has been proposed as promising approach to treating some type of cancer [14-15,24,57].

Stress has been shown to activate PrRP and noradrenaline co-expressing neurons in rat NTS [39]. These cell populations innervate the PVN [42] and can thereby activate neurons that express corticotropin-releasing factor (CRF) [40]. However, only a small fraction of CRF positive cells are positive for the PrRP receptor which may indicate that the PrRP-induced activation may be a result of activation of other neuronal pathways connecting to the PVN [36]. The authors suggest that the activation of CRF containing neurons in the PVN is a result of PrRP activation of CRF containing cell bodies in the bed nucleus of the stria terminalis (BST) where a large portion of the CRF-positive cells also co-express the PrRP receptor [36]. These neurons innervate the PVN and are able to activate the CRF positive cells through CRF1 [9]. PrRP may thereby indirectly activate CRF positive cells in the PVN which leads to CRF secretion in the pituitary and subsequent release of ACTH into the circulation [40]. ACTH thereby activates MC2Rs in the adrenal medulla which leads to elevated cortisol levels (for review see [22]. This leads to stress-induced responses such as inhibition of the immune system and inhibition of further CRF secretion [45]. The effect of centrally administered PrRP on ACTH secretion could be blocked by pretreatment with CRF-antiserum which further strengthens the link between PrRP and CRF in stress response [50]. Recent studies provide direct evidence of PrRP involvement in the regulation of inflammatory and immune responses in autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, an rheumatoid arthritis [11,46].

PrRP has also been shown to decrease circulating levels of growth hormone (GH) by activating somatostatin-secreting neurons in PerVN [29]. Moreover, mutations of the PrRP receptor gene were recently found to be associated with lowered blood pressure in a UK Caucasian population [6] and PrRP has been shown to increase mean arterial blood pressure in rats after administration in the ventrolateral medulla [27].

Furthermore, PrRP has been shown to affect food intake and core body temperature [17,32-33]. Ellacott and co-workers reported that the weight loss induced by intracerebroventricular (icv) injection of PrRP-31 was similar to the effect obtained by injections of the adipocyte hormone leptin [17]. There may be an interaction between leptin and PrRP since 90% of the PrRP expressing neurons co-express the leptin receptor and PrRP mRNA levels are reduced in the obese Zucker rat (deficient in leptin receptor expression) [17]. Vergoni and co-workers did not find an effect on feeding after single injections of PrRP, although they did find a decrease in food intake after repeated administrations of PrRP but associated this with a non-specific effect since the doses gave an adverse behavioural pattern [55]. PrRP has also been shown to be down-regulated in states of negative energy balance such as fasting which is typical for an anorectic peptide [32]. As with the stress response of PrRP, the food intake response seems to be connected to CRF since co-administration of PrRP and astressin, a CRF1 receptor antagonist, blocked the effect of PrRP [33]. CRF1 receptor antagonists also partially block the effect of leptin, which indicates that CRF may connect the PrRP and the leptin pathways. Leptin also mediates feeding through the melanocortin system, something that PrRP does not seem to do [33].

PrRP receptor knockout mice are obese and hyperphagic, show increased levels of leptin [21] and have higher nociceptive thresholds [31]. The obese OLETF rat has recently been shown to have a non-functional PrRP receptor (start codon ATG to ATA) which may explain the observed phenotype [56]. The OLETF strain was insensitive to icv injection of PrRP while wild-type rats showed a decrease in food intake [56]. However, Sprague-Dawley or Hooded Lister rats with the same mutation responded to PrRP although no binding to 125I-PrRP was detected in brain [16]. The authors suggest that PrRP exerts the feeding effect through another receptor which they were unable to detect [16]. A previous study has addressed the promiscuous binding of PrRP to GPCRs other than the PRRP receptor [18]. They found that PrRP-20 and PrRP-31 bind with nanomolar affinity to the neuropeptide FF 2 receptor (NPFF2), while the PRRP receptor is able to discriminate between different RF-amide-containing ligands [18]. The human PrRP receptor binds PrRP with high affinity but also to neuropeptide Y (NPY) and NPY-related ligands with micromolar affinity [30]. Moreover, NPY was also able to inhibit the intracellular response evoked by PrRP, which demonstrates that the interaction between NPY and PRRP is specific [30].

Newly described implications of the receptor include proliferation of pancreatic β cells and maintenance of normal glucose homeostasis during pregnancy in mice [4,28] as well as in cartilage physiology protecting against chondrocyte apoptosis in rheumatoid arthritis [2]. Other recent studies describe PRRP receptor activity as major factor in the initiation and progression of peripartum cardiomyopathy (PPCM) [25], onset of preeclampsia [34] and recurrent miscarriage [23].


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