Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 147

regulators of GPCR activity. In fact, the effect of this mutation could only be
detected when kisspeptin signaling was declining.
A Unique Mechanism of Prolonged KISS1R Signaling
with Pathophysiological Implications
The investigation of potential mechanisms underlying the slower rate of desensiti-
zation of the Arg386Pro KISS1R eliminated the possibility that receptor internal-
ization was affected by the Arg386Pro mutation, which suggested that this mutation
affected an event downstream of receptor internalization [ 41 ]. Interestingly, the
Arg386Pro mutation also did not affect the dynamic recycling of KISS1R follow-
ing receptor internalization, which was preserved for this mutant. These fi ndings
suggest that binding of kisspeptin to newly recycled receptors plays a role in the
prolonged responsiveness of the Arg386Pro KISS1R mutant to kisspeptin. Thus,
a slower rate of degradation of the mutant receptor combined with dynamic recy-
cling of internalized Arg386Pro KISS1R may account for the increased respon-
siveness of the Arg386Pro KISS1R to kisspeptin in the absence of changes in
KISS1R internalization [ 41 ].
The proposed mechanism underlying the effect of the Arg386Pro KISS1R
mutation on receptor activity is depicted in Fig. 7.3 . Here it is shown that, at
baseline, the absolute number and relative proportions of wild type (WT) and
Arg386Pro KISS1R receptors would be similar in both the plasma membrane
and internalized compartments of a given cell. The model in Fig. 7.3 depicts 70%
of WT (top left) and of Arg386Pro (bottom left) KISS1R receptors are in the
plasma membrane at baseline; whereas 30% of the receptors in both cases are
intracellular. After ligand stimulation, the relative proportions of receptors
remain similar in the membrane and intracellular compartments for WT and
Arg386Pro KISS1R. This is consistent with the unaltered rate of receptor inter-
nalization for the Arg386Pro KISS1R mutant. However, the absolute amount of
receptors in each cell compartment after ligand stimulation is no longer similar:
a slower rate of degradation would lead to greater accumulation of the Arg386Pro
KISS1R mutant in the intracellular compartment compared to WT receptor,
which would in turn result in an increase of Arg386Pro mutant KISS1R in the
plasma membrane [ 41 ].
Decreased receptor degradation has been described as the mechanism underlying
other disease-associated mutations. In one example, a mutation associated with
gonadotropin-independent precocious puberty prevents lysosomal degradation of
the LH receptor, which is also a GPCR [ 81 ]. In this case, however, the effect of the
mutation is not mild and leads to a marked increase in receptor signaling at baseline,
which characterizes constitutive activation of the receptor.