GPR161 Membrane Protein Introduction

Introduction of GPR161

GPR161 was originally isolated from fetal brain and was later renamed GPR161 as a member of the GPCR superfamily that is commonly used by cells to sense and respond to their environment. GPR161 belongs to class A rhodopsin family, and following a large-scale phylogenetic analysis, the human GPR161 was assigned to the δ group of the RHODOPSIN family within the purine receptor cluster that includes several known receptors which bind such diverse ligands as nucleotides, leukotrienes, and thrombin.

Function of GPR161 Membrane Protein

GPR161 is the key negative regulator of Shh signaling, which promotes the processing of GLI3 into GLI3R during neural tube development. GPR161 is recruited by the IFT-A complex and TULP3 to primary cilia, it functions as a regulator of the PKA-dependent basal repression machinery in Shh signaling by increasing cAMP levels, leading to promote the PKA-dependent processing of GLI3 into GLI3R and repress the Shh signaling. Furthermore, GPR161 displays restricted expression to the lateral neural folds, developing lens, retina, limb, and CNS. In presence of SHH, GPR161 is removed from primary cilia and is internalized into recycling endosomes, preventing its activity and allowing activation of the Shh signaling. Besides, A C-terminal truncation (deletion) mutation in GPR161 causes congenital cataracts and neural tube defects in the vacuolated lens (vl) mouse mutant. These previous studies identified GPR161 as a new receptor-ligand mediated pathway necessary for neural tube closure and lens development.

Fig.1 Basal activity of Gpr161 results in increased cAMP levels.

Application of GPR161 Membrane Protein in Literature

1. Mukhopadhyay S., et al. The Ciliary G-Protein-Coupled Receptor Gpr161 Negatively Regulates the Sonic Hedgehog Pathway via cAMP Signaling. Cell. 2013, 152(1-2):210 PubMed ID: 23332756
   
   

   This article describes that G-protein-coupled receptor 161 localizes to primary cilia in a Tulp3/IFT-A-dependent manner. Complete loss of GPR161 in mouse causes midgestation lethality and increased Shh signaling in the neural tube, phenocopying Tulp3/IFT-A mutants. Constitutive GPR161 activity increases cAMP levels and represses Shh signaling by determining the processing of Gli3 to its repressor form

2. Matteson P.G., et al. The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. Proceedings of the National Academy of Sciences of the United States of America. 2008, 105(6):2088-2093. PubMed ID: 18250320
   
   

   This study uses a deletion mutation in GPR161 to reveal that the cloning of the vl locus has identified a previously uncharacterized GPCR-ligand pathway necessary for neural fold fusion and lens development, providing insight into the molecular regulation of these developmental processes, and reveal that GPR161 interacts with a genetic modifier, Foxe3, to regulate lens development.

3. Feigin M.E., et al. G-protein-coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion. Proceedings of the National Academy of Sciences of the United States of America. 2014, 111(11):4191-4196. PubMed ID: 24599592
   
   

   This article identifies the orphan GPCR, GPR161, as an important regulator and a potential drug target for TNBC. GPR161 forms a signaling complex with the scaffold proteins β-arrestin 2 and Ile Gln motif containing GTPase Activating Protein 1, a regulator of mammalian target of rapamycin complex 1 and E-cadherin. Consistently, GPR161 amplified breast tumors and cells overexpressing GPR161 activate mammalian target of rapamycin signaling and decrease Ile Gln motif containing GTPase Activating Protein 1 phosphorylation.

4. Li B.I., et al. The orphan GPCR, Gpr161, regulates the retinoic acid and canonical Wnt pathways during neurulation. Developmental Biology. 2015, 402(1):17-31. PubMed ID: 25753732
   
   

   This study demonstrates the Modifier of the vacuolated lens (vl) congenic rescues the GPR161(vl)-associated lethality and NTDs but not cataracts.

5. Bachmann V.A., et al. Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling. Proceedings of the National Academy of Sciences of the United States of America. 2016, 113(28):7786-7791. PubMed ID: 27357676
   
   

   This article proposes that GPR161 is itself an AKAP and that the cAMP-sensing GPR161: PKA complex acts as cilium-compartmentalized signalosome, a concept that now needs to be considered in the analyzing, interpreting, and pharmaceutical targeting of PKA-associated functions.

GPR161 Preparation Options

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