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Vol. 281, Issue 2, 629-633, 1997
Departments of
Medicine and Microbiology-Immunology, University of
California, San Francisco, California (M.X., S.P.S., G.O.G., E.J.G),
and
Department of Molecular Sciences, Hoffmann-La Roche, Inc., Nutley,
New Jersey (D.R.B.)
Ro 25-1392
[Ac-Glu8,OCH3-Tyr10,Lys12,Nle17,Ala19,Asp25,Leu26,-
Lys27,28-vasoactive intestinal peptide(cyclo 21-25)] is a
cyclic peptide analog of vasoactive intestinal peptide (VIP) that
potently exerts cellular effects typical of VIP. The selectivity of Ro
25-1392 for type I (VIPR1) and type II (VIPR2) VIP receptors was
investigated first in competitive binding studies using Chinese hamster
ovary cell transfectants stably expressing recombinant human VIPR1 and
VIPR2. Nonradioactive Ro 25-1392 was as potent a competitive inhibitor as VIP for the binding of 125I-VIP to VIPR2 transfectants
(Ki = 9.6 ± 1.0 and 16 ± 1.7 nM, respectively; mean ± S.E.M., n = 4). In
contrast, Ro 25-1392 had a very low affinity for VIPR1, compared with
VIP, and attained a maximum of only 40% mean inhibition of binding of
125I-VIP at 1 µM. The affinity of VIP
(Ki = 3.4 ± 1.5 nM, mean ± S.E.M., n = 4) for binding to VIPR1 was 1000-fold
greater than that of Ro 25-1392. Ro 25-1392 evoked concurrent and
concentration-dependent increases in intracellular levels of calcium
and cyclic AMP (EC50 = 3.0 ± 0.4 nM, mean ± S.E.M., n = 4) in VIPR2 transfectants, but not in
VIPR1 transfectants. The VIP receptor specificity of Ro 25-1392 was
confirmed by preincubation of Chinese hamster ovary transfectants with
0.1 µM Ro 25-1392 for 18 hr at 37°C, to down-regulate each type of
VIP receptor. Pretreatment of VIPR2 transfectants with Ro 25-1392
decreased Bmax by a mean of 58% and
VIP-induced increases in the intracellular concentration of cyclic AMP
by a mean of 65%. In contrast, there was no significant change in VIPR1 transfectants after pretreatment with Ro 25-1392. Ro 25-1392 thus is selectively recognized by VIPR2, with consequent initiation of
cyclic AMP and Ca++ signals and down-regulation of VIPR2.
This potent analog of VIP may prove useful for investigations of
VIPR2-mediated physiological effects of VIP and exploration of the
roles of VIPR2 in diseases.
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