TY - JOUR
T1 - Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake
AU - Wardman, Jonathan H.
AU - Gomes, Ivone
AU - Bobeck, Erin N.
AU - Stockert, Jennifer A.
AU - Kapoor, Abhijeet
AU - Bisignano, Paola
AU - Gupta, Achla
AU - Mezei, Mihaly
AU - Kumar, Sanjai
AU - Filizola, Marta
AU - Devi, Lakshmi A.
N1 - Funding Information:
We thank K. Gagnidze for technical support and members of the Devi Laboratory for active scientific discussions. Computations were run on resources available through the Scientific Computing Facility at Mount Sinai and the Extreme Science and Engineering Discovery Environment under MCB080109N (to M.F.), which is supported by National Science Foundation grant number OCI-1053575.
PY - 2016/5/31
Y1 - 2016/5/31
N2 - Several neuropeptide systems in the hypothalamus, including neuropeptide Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated in the regulation of body weight, also control food intake. GPR171 is a heterotrimeric guanine nucleotide-binding protein (G protein)- coupled receptor (GPCR) for BigLEN (b-LEN), a peptide derived from proSAAS. To facilitate studies exploring the physiological role of GPR171, we sought to identify small-molecule ligands for this receptor by performing a virtual screen of a compound library for interaction with a homology model of GPR171. We identified MS0015203 as an agonist of GPR171 and demonstrated the selectivity of MS0015203 for GPR171 by testing the binding of this compound to 80 other membrane proteins, including family A GPCRs. Reducing the expression of GPR171 by shRNA (short hairpin RNA)-mediated knockdown blunted the cellular and tissue response to MS0015203. Peripheral injection of MS0015203 into mice increased food intake and body weight, and these responses were significantly attenuated in mice with decreased expression of GPR171 in the hypothalamus. Together, these results suggest that MS0015203 is a useful tool to probe the pharmacological and functional properties of GPR171 and that ligands targeting GPR171 may eventually lead to therapeutics for food-related disorders.
AB - Several neuropeptide systems in the hypothalamus, including neuropeptide Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated in the regulation of body weight, also control food intake. GPR171 is a heterotrimeric guanine nucleotide-binding protein (G protein)- coupled receptor (GPCR) for BigLEN (b-LEN), a peptide derived from proSAAS. To facilitate studies exploring the physiological role of GPR171, we sought to identify small-molecule ligands for this receptor by performing a virtual screen of a compound library for interaction with a homology model of GPR171. We identified MS0015203 as an agonist of GPR171 and demonstrated the selectivity of MS0015203 for GPR171 by testing the binding of this compound to 80 other membrane proteins, including family A GPCRs. Reducing the expression of GPR171 by shRNA (short hairpin RNA)-mediated knockdown blunted the cellular and tissue response to MS0015203. Peripheral injection of MS0015203 into mice increased food intake and body weight, and these responses were significantly attenuated in mice with decreased expression of GPR171 in the hypothalamus. Together, these results suggest that MS0015203 is a useful tool to probe the pharmacological and functional properties of GPR171 and that ligands targeting GPR171 may eventually lead to therapeutics for food-related disorders.
UR - http://www.scopus.com/inward/record.url?scp=84973131381&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aac8035
DO - 10.1126/scisignal.aac8035
M3 - Article
C2 - 27245612
AN - SCOPUS:84973131381
SN - 1945-0877
VL - 9
JO - Science Signaling
JF - Science Signaling
IS - 430
M1 - RA55
ER -