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Vol. 285, Issue 1, 216-222, April 1998
Departments of
Pharmacology (J.B.T., S.M.W., R.R.N.) and
Internal
Medicine/Hypertension (R.R.N.), The University of Michigan, Ann Arbor,
Michigan and the
Department of Pharmacology and Therapeutics (M.N.S.,
J.K.H.), University of Florida, Gainesville, Florida
Peptides from the intracellular regions of G protein-coupled receptors
are useful probes of receptor-G protein coupling mechanisms. As a first
step toward the genetic delivery of such "G protein inhibitors," we
describe inhibition of angiotensin II (AII) receptor responses by
expressed fragments of the second and third intracellular loops of the
AT1a receptor (AT1a/i2 and AT1a/i3). Transient transfection of human
embryonic kidney 293 cells with DNA encoding the rat AT1a receptor
resulted in AII-dependent increases of inositol phosphates (maximum
4.5-fold). Cotransfection of AT1a/i2 and AT1a/i3 fragments raised the
EC50 for AII stimulation of phospholipase C activity 5-fold
(from 0.18 nM to 0.99 nM, n = 12, P < .001) and
3-fold (from 0.38 nM to 1.2 nM, n = 8, P < .002),
respectively. The combined effect of AT1a/i2 and AT1a/3 was additive,
and transfection of an alpha-1b adrenergic receptor third
intracellular loop (
1b/i3) fragments also increased the
EC50 for AII. Neither AT1a/i1 nor C-terminus
(AT1a/Ct) constructs had significant effects on angiotensin responses. These data confirm a role for the second and third intracellular loops in angiotensin receptor responses and show the
potential of this approach to blocking multiple phospholipase C-linked
receptors.
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