GPR173 (Also known as Super-Conserved Receptor Expressed in Brain 3, or SREB3) is a highly conserved G protein-coupled receptor (GPCR) that plays a significant role in the regulation of thehypothalamic-pituitary-gonadal (HPG) axis, which is central to reproductive function.[7][8][9] It is expressed in the brain and ovaries, where it is considered the putative receptor for the peptide hormonephoenixin (PNX).
Activation of GPR173 by phoenixin potentiates the secretion ofluteinizing hormone (LH) in response togonadotropin-releasing hormone (GnRH), thereby promoting ovarian cycling and supporting reproductive processes.[8][9] Beyond reproduction, GPR173 has been implicated in diverse physiological functions such as food intake regulation, learning and memory, anxiety, inflammatory responses, and cardiac protection, largely through its modulation by phoenixin.[9]
Additionally, GPR173 may act as a receptor forcholecystokinin (CCK) in certain brain regions, mediating inhibitorysynaptic plasticity and potentially serving as a therapeutic target for disorders involving excitation-inhibition imbalance.[10] The expression of GPR173 can be influenced by nutritional and environmental factors, indicating its role as a sensor and mediator in integrating external signals withneuroendocrine pathways.[7]
Recent studies have found GPR173 may act as a receptor for the peptides phoenixin-14 (PNX-14) and phoenixin-20 (PNX-20).[11][12][8] Both Phoenixins are alternate cleavage products ofSMIM20.[11] PNX-20 treatments increased CREB phosphylation (pCREB)[13][14][15][16] and ERK1/2 phosphorylation (pERK1/2)[14] in various cell lines. These effects of PNX-20 were found to be dependent on GPR173 expression[14]. PNX-14 treatments were found to increase intracellular cAMP treatments under specific conditions within adipocytes[17]. As a ligand for GPR173, PNX-20 was found to have self regulatory behaviors by increasing GPR173 expression[16][15].
GnRH-(1-5) is a degradation product of GnRH. GnRH-(1-5) was found to induce STAT3 phosphorylation (pSTAT3) in GN11 cells[18]. GnRH-(1-5) was not found to affect cAMP levels or IP1 levels in GN11 cells, and did not recruit Gα12 or Gα13 to GPR173[19]. Activation of a G subunit associated pathway could not be confirmed, however GnRH-(1-5) treatments did have GPR173 recruit β-Arrestin 2 and PTEN[19]. GnRH-(1-5) induced production of pSTAT3 via GPR173 was found to be dependent on PTEN activity[19].
CCK8 has been found to interact with GPR173 in cell surface binding assays utilizing Flag-Tag assays[10]. CCK1R and CCK2R are established receptors for CCk8 that signal through Gαq/11. In GPR173+/+ CHO cells, CCK8 was found to mobilize [Ca2+]i with similar EC50 compared to CCK1R and CCK2R[10].
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Matsumoto M, Saito T, Takasaki J, Kamohara M, Sugimoto T, Kobayashi M, et al. (Jul 2000). "An evolutionarily conserved G-protein coupled receptor family, SREB, expressed in the central nervous system".Biochemical and Biophysical Research Communications.272 (2):576–582.Bibcode:2000BBRC..272..576M.doi:10.1006/bbrc.2000.2829.PMID10833454.
^abMcIlwraith EK, Loganathan N, Belsham DD (April 2019). "Regulation of Gpr173 expression, a putative phoenixin receptor, by saturated fatty acid palmitate and endocrine-disrupting chemical bisphenol A through a p38-mediated mechanism in immortalized hypothalamic neurons".Molecular and Cellular Endocrinology.485:54–60.doi:10.1016/j.mce.2019.01.026.PMID30716364.
