In human myometrial cells, the promiscuous coupling of the oxytocin receptors (OTRs) to G(q) and G(i) leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G(i) inhibits, whereas its coupling to G(q) stimulates, cell proliferation. Drug analogues capable of promoting a selective receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an oxytocin derivative that acts as a competitive antagonist on OTR/G(q) coupling, displays agonistic properties on OTR/G(i) coupling, as shown by specific S-35-labeled guanosine 5'-3-O-(thio) trisphosphate ([S-35] GTP gamma S) binding. Moreover, atosiban, by acting on a G(i)-mediated pathway, inhibits cell growth of HEK293 and Madin-Darby canine kidney cells stably transfected with OTRs and of DU145 prostate cancer cells expressing endogenous OTRs. Notably, atosiban leads to persistent ERK1/2 activation and p21(WAF1/CIP1) induction, the same signaling events leading to oxytocin-mediated cell growth inhibition via a Gi pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the oxytocin-induced activation of the G(q)-phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled receptor, thereby leading to the selective activation of a unique intracellular signal cascade.

Reversi, A., Rimoldi, V., Marrocco, T., Cassoni, P., Bussolati, G., Parenti, M., et al. (2005). The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 280(16), 16311-16318 [10.1074/jbc.M409945200].

The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism

PARENTI, MARCO DOMENICO;
2005

Abstract

In human myometrial cells, the promiscuous coupling of the oxytocin receptors (OTRs) to G(q) and G(i) leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G(i) inhibits, whereas its coupling to G(q) stimulates, cell proliferation. Drug analogues capable of promoting a selective receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an oxytocin derivative that acts as a competitive antagonist on OTR/G(q) coupling, displays agonistic properties on OTR/G(i) coupling, as shown by specific S-35-labeled guanosine 5'-3-O-(thio) trisphosphate ([S-35] GTP gamma S) binding. Moreover, atosiban, by acting on a G(i)-mediated pathway, inhibits cell growth of HEK293 and Madin-Darby canine kidney cells stably transfected with OTRs and of DU145 prostate cancer cells expressing endogenous OTRs. Notably, atosiban leads to persistent ERK1/2 activation and p21(WAF1/CIP1) induction, the same signaling events leading to oxytocin-mediated cell growth inhibition via a Gi pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the oxytocin-induced activation of the G(q)-phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled receptor, thereby leading to the selective activation of a unique intracellular signal cascade.
Articolo in rivista - Articolo scientifico
oxytocine
English
22-apr-2005
280
16
16311
16318
none
Reversi, A., Rimoldi, V., Marrocco, T., Cassoni, P., Bussolati, G., Parenti, M., et al. (2005). The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 280(16), 16311-16318 [10.1074/jbc.M409945200].
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/5356
Citazioni
  • Scopus 109
  • ???jsp.display-item.citation.isi??? 98
Social impact