CONICET | Buscador de Institutos y Recursos Humanos

GHSR1a is a G protein coupled receptor with constitutive activity that modulates neuronal circuits that control appetite. Thus, its inverse agonists are potential therapeutic agents that could lower the set point for hunger. Substance P analog (SP) has been extensively used in research to reduce GHSR1a constitutive activity but this peptide is highly unspecific. Therefore, there is a great interest in developing specific GHSR1a inverse agonists. Here we present a compelling study of JMV4957 (JMV), a new compound recently synthetized with potential GHSR1a inverse agonist properties.We first tested if JMV is able of binding GHSR1a in HEK293t transfected cells, and found that it has a high binding affinity (Ka=28 nM). Next we explored the inverse agonist effect of JMV and found that this compound induced a 20% reduction of the basal inositol phosphate production with a EC50=35nM in HEK293t cells expressing GHSR1a. Moreover, we explored the effect of JMV on the previously described inhibitory effect of GHSR1a constitutive activity on voltage-gated calcium channels basal currents (ICa) and surface channel expression. We found that pre-incubation with JMV avoided this effect in the same manner as SP. We also performed imaging experiments and found that JMV recovers channel surface density to control values in cells transfected with GHSR1a and GFP tagged channels. We are currently testing JMV effect on ghrelin-induced food intake on mice.