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(Received for publication, January 23, 1997, and in revised form, May 5, 1997)
From the Departments of Biochemistry and Molecular Pharmacology,
and Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson
University, Philadelphia, Pennsylvania 19107 and the
G protein-coupled receptor kinases (GRKs)
specifically phosphorylate and regulate the activated form of multiple
G protein-coupled receptors. Recent studies have revealed that GRKs are
also subject to regulation. In this regard, GRK2 and GRK5 can be
phosphorylated and either activated or inhibited, respectively, by
protein kinase C. Here we demonstrate that calmodulin, another mediator
of calcium signaling, is a potent inhibitor of GRK activity with a
selectivity for GRK5 (IC50 ~50 nM) > GRK6
Volume 272, Number 29,
Issue of July 18, 1997
pp. 18273-18280
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
,
and
Department of Molecular and Cellular Pharmacology,
University of Miami School of Medicine, Miami, Florida 33136
GRK2 (IC50 ~2 µM) GRK1.
Calmodulin inhibition of GRK5 is mediated via a reduced ability of the
kinase to bind to both receptor and phospholipid. Interestingly,
calmodulin also activates autophosphorylation of GRK5 at sites distinct
from the two major autophosphorylation sites on GRK5. Moreover,
calmodulin-stimulated autophosphorylation directly inhibits GRK5
interaction with receptor even in the absence of calmodulin. Using
glutathione S-transferase-GRK5 fusion proteins either to
inhibit calmodulin-stimulated autophosphorylation or to bind directly
to calmodulin, we determined that an amino-terminal domain of GRK5
(amino acids 20-39) is sufficient for calmodulin binding. This domain
is abundant in basic and hydrophobic residues, characteristics typical
of calmodulin binding sites, and is highly conserved in GRK4, GRK5, and
GRK6. These studies suggest that calmodulin may serve a general role in
mediating calcium-dependent regulation of GRK activity.
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