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J Biol Chem, Vol. 273, Issue 22, 13613-13624, May 29, 1998
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From the Bombesin (Bn) receptor subtype 3 (BRS-3) is an
orphan receptor that is a predicted member of the heptahelical
G-protein receptor family and so named because it shares a 50% amino
acid homology with receptors for the mammalian bombesin-like peptides
neuromedin B (NMB) and gastrin-releasing peptide. In a recent targeted
disruption study, in which BRS-3-deficient mice were generated, the
mice developed obesity, diabetes, and hypertension. To date, BRS-3's natural ligand remains unknown, its pharmacology unclear, and cellular
basis of action undetermined. Furthermore, there are few tissues or
cell lines found that express sufficient levels of BRS-3 protein for
study. To define the intracellular signaling properties of BRS-3, we
examined the ability of
[D-Phe6, Digestive Diseases Branch, NIDDK, National
Institutes of Health, Bethesda, Maryland 20892, § NIDCD,
National Institutes of Health, Rockville, Maryland 20892, and
¶ Peptide Research Laboratories, Tulane University Medical
Center, New Orleans, Louisiana 70112
-Ala11,Phe13,Nle14]Bn-(6-14),
a newly discovered peptide with high affinity for BRS-3, and various Bn
receptor agonists and antagonists to alter cellular function in
hBRS-3-transfected BALB 3T3 cells and hBRS-3-transfected NCI-H1299
non-small cell lung cancer cells, which natively express very low
levels of hBRS-3. This ligand stimulated a 4-9-fold increase in
[3H]inositol phosphate formation in both cell lines under
conditions where it caused no stimulation in untransfected cells and
also stimulated an increase in [3H]IP1,
[3H]IP2, and 3H]IP3.
The elevation of [3H]IP was
concentration-dependent, with an EC50 of 20-35
nM in both cell lines.
[D-Phe6,-Ala11,Phe13,Nle14]Bn-(6-14)
stimulated a 2-3-fold increase in [Ca2+]i, a
3-fold increase in tyrosine phosphorylation of p125FAK with
an EC50 of 0.2-0.7 nM, but failed to either
stimulate increases in cyclic AMP or inhibit forskolin-stimulated
increases. None of nine naturally occurring Bn peptides or three
synthetic Bn analogues reported to activate hBRS-3 did so with high
affinity. No high affinity Bn receptor antagonists had high affinity
for the hBRS-3 receptor, although two low affinity antagonists
for gastrin-releasing peptide and NMB receptors,
[D-Arg1,D-Trp7,9,Leu11]substance
P and
[D-Pro4,D-Trp7,9,10]substance
P-(4-11), inhibited hBRS-3 receptor activation. The NMB
receptor-specific antagonist
D-Nal,Cys,Tyr,D-Trp,Lys,Val, Cys,Nal-NH2 inhibited hBRS-3 receptor activation in a
competitive fashion (Ki = 0.5 µM).
Stimulation of p125FAK tyrosine phosphorylation by hBRS-3
activation was not inhibited by the protein kinase C inhibitor,
GF109203X, or thapsigargin, alone or in combination. These results show
that hBRS-3 receptor activation increases phospholipase C activity,
which causes generation of inositol phosphates and changes in
[Ca2+]i and is also coupled to tyrosine kinase
activation, but is not coupled to adenylate cyclase activation or
inhibition. hBRS-3 receptor activation results in tyrosine
phosphorylation of p125FAK, and it is not dependent on
activation of either limb of the phospholipase C cascade. Although the
natural ligand is not a known bombesin-related peptide, the
availability of
[D-Phe6,-Ala11,Phe13,Nle14]Bn-(6-14),
which functions as a high affinity agonist in conjunction with
hBRS-3-transfected cell lines and the recognition of three classes of
receptor antagonists including one with affinity of 0.5 µM, should provide important tools to assist in the
identification of its natural ligand, the development of more potent
selective receptor antagonists and agonists, and further exploration of the signaling properties of the hBRS-3 receptor.
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