CHARACTERIZATION OF THE EFFECT OF SR48692 ON INOSITOL MONOPHOSPHATE, CYCLIC-GMP AND CYCLIC-AMP RESPONSES LINKED TO NEUROTENSIN RECEPTOR ACTIVATION IN NEURONAL AND NONNEURONAL CELLS
F. Ourydonat et al., CHARACTERIZATION OF THE EFFECT OF SR48692 ON INOSITOL MONOPHOSPHATE, CYCLIC-GMP AND CYCLIC-AMP RESPONSES LINKED TO NEUROTENSIN RECEPTOR ACTIVATION IN NEURONAL AND NONNEURONAL CELLS, British Journal of Pharmacology, 116(2), 1995, pp. 1899-1905
1 Neurotensin stimulated inositol monophosphate (IP1) formation in bot
h human colonic carcinoma HT29 cells and in mouse neuroblastoma N1E115
cells with EC(50) values of 3.5+/-0.5 nM (n=4) and 0.46+/-0.02 nM (n=
3), respectively. Neurotensin also stimulated cyclic GMP production wi
th an EC(50) of 0.47+/-1.2 nM and inhibited cyclic AMP accumulation in
duced by forskolin (0.5 mu M) with an IC50 Of 1.33+/-1.5 nM (n=3) on t
he N1E115 cell line. 2 The competitive antagonism by the non-peptide n
eurotensin receptor antagonist, SR48692 of neurotensin-induced IPI for
mation revealed pA(2) values of 8.7+/-0.2 (n=3) for HT29 and 10.1+/-0.
2 (n=3) for N1E115 cells. SR48692 also antagonized the cyclic GMP and
cyclic AMP responses induced by neurotensin in the N1E115 cell line wi
th pA(2) values of 10.7+/-0.7 (n=3) and 9.8+/-0.3 (n=3), respectively.
3 In CHO cells transfected with the rat neurotensin receptor, neurote
nsin stimulated IP1 and cyclic AMP formation with EC(50) values of 3.0
+/-0.5 nM (n=3) and 72.2+/-20.7 nM (n=3), respectively. Both effects w
ere antagonized by SR48692, giving pA(2) values of 8.4+/-0.1 (n=3) for
IP1 and 7.2+/-0.4 (n=3) for cyclic AMP responses. 4 Radioligand bindi
ng experiments, performed with [I-125]-neurotensin (0.2 nM), yielded I
C50 values of 15.3 nM (n=2) and 20.4 nM (n=2) for SR48692 versus neuro
tensin receptor binding sites labelled in HT29 and N1E115 cells, respe
ctively. 5 In conclusion, SR48692 appears to be a potent, species-inde
pendent antagonist of the signal transduction events triggered by neur
otensin receptor activation in both neuronal and non-neuronal cell sys
tems.