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J. Biol. Chem., Vol. 276, Issue 30, 28083-28091, July 27, 2001
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From the Substance P analogues including
[D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance
P (SpD) act as "broad spectrum neuropeptide antagonists" and are
potential anticancer agents that inhibit the growth of small cell lung
cancer cells in vitro and in vivo.
However, their mechanism of action is controversial and not fully
understood. Although these compounds block bombesin-induced mitogenesis
and signal transduction, they also have agonist activity. The mechanism underlying this agonist activity was examined. SpD binds to the ligand-binding site of the bombesin/gastrin-releasing peptide receptor
and blocks the bombesin-stimulated increase in
[Ca2+]i within the same concentration range
that causes sustained activation of c-Jun N-terminal kinase and
extracellular signal-regulated protein kinase (ERK). The activation of
c-Jun N-terminal kinase by SpD and bombesin is blocked by dominant
negative inhibition of G
Bombesin and Substance P Analogues Differentially Regulate
G-protein Coupling to the Bombesin Receptor
DIRECT EVIDENCE FOR BIASED AGONISM*
,§,¶,, and
Rayne Laboratory, Centre for Inflammation
Research, Respiratory Medicine Unit, University of Edinburgh Medical
School, Teviot Place, Edinburgh, EH8 9AG, United Kingdom and the
¶ Imperial Cancer Research Fund, Medical Oncology Unit,
Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, United
Kingdom
12. The ERK activation by SpD is
pertussis toxin-sensitive in contrast to ERK activation by
bombesin, which is pertussis toxin-insensitive but dependent on
epidermal growth factor receptor phosphorylation. SpD
does not simply act as a partial agonist but differentially modulates
the activation of the G-proteins G12,
Gi, and Gq compared with bombesin. This unique
ability allows the bombesin receptor to couple to Gi and at
the same time block receptor activation of Gq. Our results
provide direct evidence that SpD is acting as a "biased agonist"
and that this has physiological relevance in small cell lung cancer
cells. This validation of the concept of biased agonism has important
implications in the development of novel pharmacological agents to
dissect receptor-mediated signal transduction and of highly selective
drugs to treat human disease.
*
This work was supported in part by Scottish Hospitals
Endowment Research Trust Grant SHERT 1441 and the Melville Trust for the Care and Cure of Cancer.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a Wellcome Trust Research Leave Fellowship. To
whom correspondence should be addressed. Tel.: 0044-131-650-6947; Fax.:
0044-131-650-4384; E-mail: T.sethi@ed.ac.uk.
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