Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 148

Fig. 7.3 Model of KISS1R desensitization. At baseline, absolute numbers and relative propor-
tions of wild type (WT) and Arg386Pro KISS1R would be similar in both the plasma membrane
and internalized compartments of a given cell. In this model, 70% of WT ( top left ) and of
Arg386Pro ( bottom left ) receptors are in the plasma membrane whereas the remaining 30% of the
receptors in both cases are intracellular. After 120 min of ligand stimulation, relative proportions
of receptors remain similar in the membrane and intracellular compartments for WT and Arg386Pro
KISS1R, whereas absolute number is no longer similar, with the Arg386Pro KISS1R mutant
exhibiting higher absolute number of receptors in both the membrane and intracellular compart-
ments compared to WT KISS1R. From Bianco SD, Vandepas L, Correa-Medina M, Gereben B,
Mukherjee A, Kuohung W, Carroll R, Teles MG, Latronico AC, Kaiser UB (2011) KISS1R intra-
cellular traffi cking and degradation: effect of the Arg386Pro disease-associated mutation.
Endocrinology 152:1616-1626. (Reprinted with permission from The Endocrine Society)
A Little Gain-of-Function Goes a Long Way
The mild gain of function conferred by the Arg386Pro KISS1R mutation, combined
with the requirement for ligand activation for the appearance of the effect of this
mutation, are predicted to be key details determining the manifestation of the preco-
cious puberty phenotype in the affected patient. This is based on the kinetics of
KISS1R activity, which shows that continuous stimulation leads to a peak of activity
followed by complete desensitization of KISS1R signaling [ 41 ]. This desensitiza-
tion can be detected in vivo as suppression of gonadotropin secretion in primates
[ 48 ] or testicular degeneration in rats [ 49 ]. An implication of this behavior is that con-
stitutive activation of KISS1R is expected to lead to an IHH phenotype rather than