Ca2+ channel blockers enhance neurotensin (NT) binding and inhibit NT-induced inositol phosphate formation in prostate cancer PC3 cells
UMass Chan Affiliations
Department of PhysiologyDocument Type
Journal ArticlePublication Date
2003-10-23Keywords
Binding SitesCalcium
Calcium Channel Blockers
Endocytosis
Enzyme Inhibitors
Epidermal Growth Factor
Humans
Inositol Phosphates
Iodine Radioisotopes
Male
Neurotensin
Nifedipine
Photoaffinity Labels
Prostatic Neoplasms
Protein-Tyrosine Kinases
Receptors, Neurotensin
Tumor Cells, Cultured
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Neurotensin (NT) stimulates Ca2+ release and Ca2+ influx in many cells. Its contractile effects in smooth muscle are inhibited by removal of Ca2+ and by Ca2+ channel blockers (CCBs). To better understand NT signaling in prostate cancer PC3 cells, blockers of voltage-gated and store-operated Ca2+ channels (VGCC and SOCC) were tested for effects on NT-binding and signaling. Eight chemical types of agents, including VGCC-blocker nifedipine and SOCC-blocker SKF-96365 (1-[beta-[3-(4-methoxyphenyl)-propoxy]-4-methoxyphenyl]-1H-imidazole), enhanced cellular NT binding up to 3-fold, while inhibiting (by congruent with 70%) NT-induced inositol phosphate (IP) formation. The ability to enhance NT binding correlated with the ability to inhibit NT-induced IP formation, and both effects were relatively specific for NT. Although cellular binding for beta2-adrenergic, V1a-vasopressin, and epidermal growth factor receptors was not enhanced by these drugs, bombesin receptor binding was increased approximately equal to 19% and bombesin-induced IP formation was inhibited approximately equal to 15%. One difference was that the effect on NT binding was Ca2+-independent, whereas the effect on IP formation was Ca2+-dependent (in part). The Ca2+-dependent part of the IP response seemed to involve SOCC-mediated Ca2+ influx to activate phospholipase C (PLC)delta, while the Ca2+-independent part probably involved PLCbeta. Photoaffinity labeling of the NT receptor NTR1 was enhanced in CCB-treated cells. NTR1 affinity was increased but NTR1 number and internalization were unchanged. Since CCBs did not alter NT binding to isolated cell membranes, the effects in live cells were indirect. These results suggest that CCBs exert two effects: 1) they inhibit NT-induced IP formation, perhaps by preventing Ca2+ influx-dependent activation of PLCdelta; and 2) they enhance NTR1 affinity by an unexplained Ca2+-independent mechanism.Source
J Pharmacol Exp Ther. 2003 Nov;307(2):640-50. Link to article on publisher's site
DOI
10.1124/jpet.102.052688Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38618PubMed ID
14570823Related Resources
ae974a485f413a2113503eed53cd6c53
10.1124/jpet.102.052688