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Targeting V 1A ‐vasopressin receptors with [Arg 6 , D‐Trp 7,9 , N me Phe 8 ]‐substance P (6‐11) identifies a strategy to develop novel anti‐cancer therapies
Author(s) -
MacKin Alison C.,
TufailHanif Uzma,
Wheatley Mark,
Rossi Adriano G.,
Haslett Christopher,
Seckl Michael,
Sethi Tariq
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00003.x
Subject(s) - receptor , pertussis toxin , agonist , vasopressin , phospholipase c , biology , mapk/erk pathway , vasopressin receptor , microbiology and biotechnology , intracellular , extracellular , g protein , endocrinology , medicine , signal transduction , biochemistry , antagonist
Background and purpose: The anti‐cancer agent [Arg 6 , D‐Trp 7,9 , N me Phe 8 ]‐substance P (6‐11) (SP‐G) modulates gastrin releasing peptide (GRP) and arginine vasopressin signalling in small cell lung cancer cells leading to growth arrest and apoptosis. We have shown that SP‐G acts as a biased agonist at GRP receptors. This work examines the hypothesis that SP‐G acts as a biased agonist at the V 1A vasopressin receptor. Experimental approach: The human V 1A receptor was expressed in CHO‐K1 cells. Extracellular regulated kinase (ERK) activation and intracellular Ca 2+ were measured using activation state‐specific antibodies and Fura‐2‐AM respectively. The effect of SP‐G on tumourigenicity was assessed by colony assay. Key results: In V 1A receptor expressing cells, SP‐G caused a sustained activation of ERK via a stimulation of V 1A receptor coupling to G i . Inhibition of G i with Pertussis toxin attenuated the inhibition by SP‐G of the growth of CHO‐K1 cells stably expressing the V 1A receptor. Chimeric V 1A receptors containing the second or third intracellular loop of the V 2 receptor were capable of binding vasopressin and SP‐G but had altered ability to activate phospholipase C (PLC) and ERK. The second intracellular loop of the V 1A receptor was essential for vasopressin‐stimulated PLC and ERK activation but not for SP‐G‐induced ERK activation. Conclusions and implications: This work provides mechanistic insight, for biased agonists at V 1A receptors and highlights a potential role for such agents as anti‐cancer agents.