Prokineticin-2

PROK2 is a key output signal of the SCN master clock. It is rhythmically expressed in SCN neurons with a peak during the light phase in nocturnal rodents, and its secretion conveys circadian timing information to downstream brain regions. ICV PROK2 suppresses locomotor activity and feeding in a phase-dependent manner, consistent with the "rest signal" role. PROKR2-deficient mice show severely disrupted circadian locomotor rhythms and altered sleep structure.

PROK2 is robustly upregulated in inflammatory conditions and activates PROKR1/R2 on dorsal root ganglia sensory neurons, lowering pain thresholds (hyperalgesia and allodynia). It activates Gi/Gq coupling, triggering PKC and MAPK phosphorylation that sensitizes TRPV1 and voltage-gated sodium channels. PROK2 is one of several mediators contributing to inflammatory pain centralization, making PROKR antagonists attractive analgesic candidates.

During embryonic development, PROK2/PROKR2 signaling is required for GnRH neuron migration from the olfactory placode to the hypothalamus and for olfactory bulb morphogenesis. Disruption causes Kallmann syndrome, characterized by anosmia and hypogonadotropic hypogonadism. PROKR2 mutations account for ~10% of Kallmann syndrome cases. This developmental role is distinct from adult neuromodulatory functions.

Exogenous PROK2 administered ICV shifts circadian phase in rodents, demonstrating its role as a clock output signal. PROKR2 knockout mice have fragmented sleep-wake cycles and blunted circadian rhythmicity. Research into PROK2 circadian modulation may yield treatments for shift-work disorder, jet lag, and circadian misalignment in metabolic disease, though no clinical candidates have advanced.

Multiple pharmaceutical companies have developed PROKR2 antagonists (PC1 series, others) that show efficacy in rodent models of inflammatory hyperalgesia, bone cancer pain, and chemotherapy-induced neuropathy. These antagonists block PROK2-mediated central sensitization without affecting acute nociception. Selectivity over PROKR1 has been a challenge in the development of clean analgesic candidates.

PROK2 (also called EG-VEGF2) promotes angiogenesis in steroidogenic glands and the corpus luteum. It supports endometrial angiogenesis during implantation and luteal development. In models of reproductive tissue remodeling, PROK2 is a critical vascular mitogen distinct from VEGF. Dysregulation of PROK2 has been studied in endometriosis, preeclampsia, and ovarian dysfunction.