Fig. 6.

Proposed model of KISS1R trafficking and effect of the Arg386Pro mutation. Under basal conditions, a similar number of receptors is detected on the membrane (seven receptors) and internalized (three receptors) fractions in cells expressing WT (top left) or Arg386Pro (bottom left) KISS1R. Relative distribution at baseline is also similar: 70% on the membrane and 30% internalized for both WT (top left) and Arg386Pro (bottom left) KISS1R. After 120 min of stimulation, relative distribution remains similar for WT (top right) and Arg386Pro (bottom right) KISS1R: 40% on the membrane and 60% internalized. However, total receptor number is no longer similar. WT KISS1R decreased to 4 on the membrane and increased to 6 internalized (top right), whereas Arg386Pro KISS1R increased on both fractions after stimulation: 11 on the membrane and 17 internalized (bottom right). A small percentage of receptors is degraded after internalization, and a reduced rate of degradation of Arg386Pro KISS1R is proposed to increase intracellular accumulation of this mutant, which combined to a dynamic recycling would be enough to account for the time-dependent magnification of kisspeptin responsiveness by this mutant. A pool of intracellular KISS1R not initially detected at baseline (in gray) is proposed to be recruited to the membrane and thus account for the apparent increases in receptor number after stimulation. Values on this figure are based on data represented in Fig. 5B.