Phoenixin: uncovering its receptor, signaling and functions

Abstract

Phoenixin (PNX) is a newly discovered peptide that has been linked to reproductive function, both in the hypothalamus and pituitary. This review will focus on the most recent discoveries related to this novel neuropeptide. Initially, it was found that PNX increased gonadotropin releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release from pituitary cells. Importantly, knockdown of PNX in female rats extended the estrous cycle by 2.3 days. Using novel hypothalamic cell lines, we found that PNX has a stimulatory role on kisspeptin (Kiss) and GnRH gene expression and secretion. The PNX receptor was uncovered using siRNA knockdown of GPR173, an orphan receptor postulated to bind PNX. We have found that the PNX-R signaling through protein kinase A (PKA) in hypothalamic neurons. Althuogh a number of studies demonstrate that PNX plays an important role in reproductive function, there is also evidence that it may have other functions, regulating the heart, feeding, memory, and anxiety, both in the brain and the periphery.

Figure 1

Summary of the proposed mechanisms involved in the regulation of gene expression by PNX in mHypoA-GnRH/GFP and mHypoA-Kiss/GFP-3 cell models. GPR173 has been identified as the cognate receptor for GPR173 (PNX-R). PNX increases the phosphorylation of CREB, suggesting that it activates a G_αs protein and the cAMP/PKA pathway. PKA was shown to be necessary to induce changes in GnRH, Kiss-1, Oct-1 and C/EBPb mRNA expression by PNX. This pathway may therefore mediate the hypothalamic changes in mRNA expression by PNX (from Treen et al).