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CELLULAR AND MOLECULAR

Ca²⁺ Channel Blockers Enhance Neurotensin (NT) Binding and Inhibit NT-Induced Inositol Phosphate Formation in Prostate Cancer PC3 Cells

Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts (R.E.C., X.G.); and Department of Biology, Tufts University, Medford, Massachusetts (D.E.C.)

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-[-[3-(4-methoxyphenyl)-propoxy]-4-methoxyphenyl]-1H-imidazole), enhanced cellular NT binding up to 3-fold, while inhibiting (by 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 ₂-adrenergic, V_1a-vasopressin, and epidermal growth factor receptors was not enhanced by these drugs, bombesin receptor binding was increased 19% and bombesin-induced IP formation was inhibited 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), while the Ca²⁺-independent part probably involved PLC. 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 PLC; and 2) they enhance NTR1 affinity by an unexplained Ca²⁺-independent mechanism.

Address correspondence to: Dr. Robert E. Carraway, Department of Physiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. E-mail: robert.carraway{at}umassmed.edu

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