Prolactin-Releasing Peptide

Overview

Prolactin-releasing peptide (PrRP) is a 31-amino-acid hypothalamic neuropeptide identified in 1998 by Hinuma and colleagues through orphan G protein-coupled receptor screening. PrRP was the first peptide ligand discovered for the previously orphan receptor GPR10. The human PrRP-31 sequence is Phe-Ser-Asp-Pro-Ser-Ser-Pro-Ser-Arg-Thr-His-Arg-His-Ser-Met-Ala-Ile-Arg-Gln-Asn-His-Glu-Ala-Asn-Lys-Val-Ala-Glu-Leu-Asn. A 20-amino-acid truncation product (PrRP-20) retains partial biological activity.

Discovery Strategy

PrRP was discovered using a functional cloning approach targeting orphan G protein-coupled receptors. GPR10 was expressed in cell lines and screened against hypothalamic cDNA libraries to identify its activating ligand. The cloned receptor was subsequently demonstrated to be expressed in the anterior pituitary, providing a mechanism for direct hypothalamic-pituitary prolactin regulation independent of classical releasing factors.

Receptor and Signaling

PrRP binds to GPR10 (also known as NMU receptor-2) with an EC50 of approximately 1 nM in calcium mobilization assays. GPR10 couples to Gq/11 proteins, activating phospholipase C and mobilizing intracellular calcium. In pituitary lactotrophs, PrRP stimulates prolactin release through calcium-dependent exocytosis. The receptor is also expressed in the hypothalamus, brainstem, and peripheral tissues.

Physiological Functions

PrRP potently stimulates prolactin secretion when administered intracerebroventricularly or intravenously, though its potency is lower than vasoactive intestinal peptide (VIP) in some species. PrRP-immunoreactive neurons are concentrated in the dorsomedial hypothalamus and project to the median eminence, establishing a direct neuroendocrine pathway. Beyond prolactin regulation, PrRP modulates feeding behavior, stress responses, and circadian rhythm.

Metabolic Regulation

PrRP neurons in the dorsomedial hypothalamus are activated by fasting and energy depletion, suggesting a role in energy homeostasis. PrRP knockout mice exhibit mild obesity with increased body weight and reduced thermogenesis, indicating involvement in sympathetic nervous system regulation of metabolic rate.

Clinical Perspectives

Altered PrRP signaling has been investigated in depression and stress-related disorders, where GPR10 expression is modulated in limbic structures. PrRP analogs may represent novel therapeutic approaches for prolactin-related reproductive disorders and metabolic syndrome, though clinical development remains in early stages.

References

1. Hinuma, S., et al. (1998). A prolactin-releasing peptide in the brain. Nature, 393(6682), 272-276.
2. Lawrence, C.B., et al. (2000). PrRP in energy homeostasis. Molecular and Cellular Endocrinology, 205(1-2), 129-139.
3. Roland, B.L., et al. (1999). Distribution and regulation of PrRP. Endocrinology, 140(8), 3713-3718.