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Department of Pharmacology (M. de F.M.L., X.L., K.N., M.A.) The
University of Iowa College of Medicine Iowa City, Iowa 52242
Department of Microbiology and Immunology (J.L.B.) Kimmel
Cancer Institute Thomas Jefferson University Philadelphia,
Pennsylvania 19107
The experiments presented herein were designed to
identify members of the G protein-coupled receptor kinase (GRK) family
that participate in the agonist-induced phosphorylation and
internalization of the rat FSH receptor (rFSHR). Western blots of human
kidney 293 cells (the cell line used in transfection experiments) and
MSC-1 cells (a cell line derived from Sertoli cells that displays many
of the differentiated functions of their normal counterparts) reveal
the presence of GRK2 and GRK6 in both cell lines as well as GRK4 in
MSC-1 cells. Cotransfection of 293 cells with the rFSHR and GRK2,
GRK4
, or GRK6 resulted in an increase in the agonist-induced
phosphorylation of the rFSHR. Cotransfections of the rFSHR with GRKs or
arrestin-3 enhanced the agonist-induced internalization of the rFHSR,
and combinations of GRKs and arrestin-3 were more effective than the
individual components. To characterize the involvement of endogenous
GRKs on phosphorylation and internalization, we inhibited endogenous
GRK2 by overexpression of a kinase-deficient mutant of GRK2 or Gt, a
scavenger of Gß
. We also inhibited endogenous GRK6 by
overexpression of a kinase-deficient mutant of GKR6. All three
constructs were effective inhibitors of phosphorylation, but only the
kinase-deficient mutant of GRK2 and Gt inhibited internalization.
The inhibition of internalization induced by these two constructs was
less pronounced than that induced by a dominant-negative mutant of the
nonvisual arrrestins, however. The finding that inhibitors of GRK2 and
GRK6 impair phosphorylation, but only the inhibitors of GRK2
impair internalization, suggests that different GRKs have
differential effects on receptor internalization.
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