{"doi":"10.1016/j.jbc.2022.101646","title":"Pharmacological chaperones for the oxytocin receptor increase oxytocin responsiveness in myometrial cells","abstract":"Oxytocin is a potent uterotonic agent administered to nearly all patients during childbirth in the United States. Inadequate oxytocin response can necessitate Cesarean delivery or lead to uterine atony and postpartum hemorrhage. Thus, it may be clinically useful to identify patients at risk for poor oxytocin response and develop strategies to sensitize the uterus to oxytocin. Previously, we showed that the V281M variant in the oxytocin receptor (OXTR) gene impairs OXTR trafficking to the cell surface, leading to a decreased oxytocin response in cells. Here, we sought to identify pharmacological chaperones that increased oxytocin response in cells expressing WT or V281M OXTR. We screened nine small-molecule agonists and antagonists of the oxytocin/vasopressin receptor family and identified two, SR49059 and L371,257, that restored both OXTR trafficking and oxytocin response in HEK293T cells transfected with V281M OXTR. In hTERT-immortalized human myometrial cells, which endogenously express WT OXTR, treatment with SR49059 and L371,257 increased the amount of OXTR on the cell surface by two- to fourfold. Furthermore, SR49059 and L371,257 increased the endogenous oxytocin response in hTERT-immortalized human myometrial cells by 35% and induced robust oxytocin responses in primary myometrial cells obtained from patients at the time of Cesarean section. If future studies demonstrate that these pharmacological chaperones or related compounds function similarly in vivo, we propose that they could potentially be used to enhance clinical response to oxytocin. Oxytocin is a potent uterotonic agent administered to nearly all patients during childbirth in the United States. Inadequate oxytocin response can necessitate Cesarean delivery or lead to uterine atony and postpartum hemorrhage. Thus, it may be clinically useful to identify patients at risk for poor oxytocin response and develop strategies to sensitize the uterus to oxytocin. Previously, we showed that the V281M variant in the oxytocin receptor (OXTR) gene impairs OXTR trafficking to the cell surface, leading to a decreased oxytocin response in cells. Here, we sought to identify pharmacological chaperones that increased oxytocin response in cells expressing WT or V281M OXTR. We screened nine small-molecule agonists and antagonists of the oxytocin/vasopressin receptor family and identified two, SR49059 and L371,257, that restored both OXTR trafficking and oxytocin response in HEK293T cells transfected with V281M OXTR. In hTERT-immortalized human myometrial cells, which endogenously express WT OXTR, treatment with SR49059 and L371,257 increased the amount of OXTR on the cell surface by two- to fourfold. Furthermore, SR49059 and L371,257 increased the endogenous oxytocin response in hTERT-immortalized human myometrial cells by 35% and induced robust oxytocin responses in primary myometrial cells obtained from patients at the time of Cesarean section. If future studies demonstrate that these pharmacological chaperones or related compounds function similarly in vivo, we propose that they could potentially be used to enhance clinical response to oxytocin. The nonapeptide hormone oxytocin modulates social behavior, mediates the lactation reflex, and induces and strengthens uterine contractions. Synthetic oxytocin is administered to induce or augment labor and prevent postpartum hemorrhage in a large portion of patients who give birth (1Martin J.A. Hamilton B.E. Osterman M.J.K. Driscoll A.K. Births: Final data for 2019.Natl. Vital Stat. Rep. 2021; 70: 1-51Google Scholar, 2American College of Obstetrics and GynecologyPractice bulletin no. 183: Postpartum hemorrhage.Obstet. Gynecol. 2017; 130: e168-e186Google Scholar). However, response to oxytocin varies widely between individuals (3Frey H.A. Tuuli M.G. England S.K. Roehl K.A. Odibo A.O. Macones G.A. Cahill A.G. Factors associated with higher oxytocin requirements in labor.J. Matern. Fetal Neonatal. Med. 2015; 28: 1614-1619Google Scholar). ","journal":"Journal of Biological Chemistry","year":2022,"id":269453,"datarank":0.5617803402220759,"base_score":2.772588722239781,"endowment":2.772588722239781,"self_citation_contribution":0.41588830833596724,"citation_network_contribution":0.14589203188610864,"self_endowment_contribution":0.41588830833596724,"citer_contribution":0.14589203188610864,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":7,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":385538,"name":"Yingye Fang","orcid":"0000-0003-4137-866X","position":1,"is_corresponding":false},{"id":792601,"name":"Monali Wakle‐Prabagaran","orcid":null,"position":2,"is_corresponding":false},{"id":729900,"name":"Michelle E. Roh","orcid":"0000-0002-6268-0801","position":3,"is_corresponding":false},{"id":932598,"name":"Kevin Prifti","orcid":"0000-0001-8411-9997","position":4,"is_corresponding":false},{"id":443490,"name":"Antonina I. Frolova","orcid":"0000-0002-6491-6910","position":5,"is_corresponding":false},{"id":230440,"name":"P. I. Imoukhuede","orcid":"0000-0002-4257-1085","position":6,"is_corresponding":false},{"id":40925,"name":"Sarah K. England","orcid":"0000-0003-4247-0281","position":7,"is_corresponding":false},{"id":729898,"name":"Manasi Malik","orcid":"0000-0002-4203-962X","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:27:22.602796Z","pmid":"35093385","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}