GnRH stimulates gonadotropin secretion, which desensitizes unless the
releasing hormone is secreted or administered in a pulsatile fashion.
The mechanism of desensitization is unknown, but as the GnRH receptor
is G protein coupled, it might involve G protein-coupled receptor kina
ses (GRKs). Such kinases phosphorylate the intracellular regions of se
ven-transmembrane receptors, permitting beta-arrestin to bind, which p
revents the receptor from activating G proteins. Here, we tested the e
ffect of GRKs and beta-arrestins on GnRH-induced inositol trisphosphat
e (IP3) production in COS cells transfected with the GnRH receptor com
plementary DNA. GRK2, -3, and -6 overexpression inhibited IP3 producti
on by 50-75% during the 30 sec of GnRH treatment. Coexpression of GRK2
and beta-arrestin-2 suppressed GnRH-induced IP3 production more than
that of either alone. Immunocytochemical staining of rat anterior pitu
itary revealed that all cells expressed GRK2, -3, and -6; all cells al
so expressed the beta-arrestins. Western blots on cytosolic extracts o
f rat pituitaries revealed the presence of GRK2/3 and beta-arrestin-1
and -2. The expression of GRKs and beta-arrestins by gonadotropes and
their inhibition of GnRH-stimulated IP3 production in COS-1 cells expr
essing the GnRH receptor suggest a potential regulatory role for the G
RK/beta arrestin paradigm in GnRH receptor signaling.