Ca2+/Calmodulin Inhibition and Phospholipase C-Linked Ca2+ Signaling in Clonalβ -Cells1

Neurotransmitters and hormones, such as arginine vasopressin (AVP) and bombesin, evoke frequency-modulated repetitive Ca2+ transients in insulin-secreting HIT-T15 cells by binding to receptors linked to phospholipase C (PLC). The role of calmodulin (CaM)-dependent mechanisms in the generation of PLC-linked Ca2+ transients was investigated by use of the naphthalenesulfonamide CaM antagonists W-7 and W-13 and their dechlorinated control analogs W-5 and W-12. W-7 (10–30μ m) and W-13 (30–100 μm), but not W-5 (100μ m) and W-12 (300 μm), reversibly inhibited the AVP- and bombesin-induced Ca2+ transients. As the generation of PLC-linked Ca2+ transients requires mobilization of internal Ca2+ and Ca2+ influx through voltage-sensitive (VSCC) and -insensitive (VICC) Ca2+ channels, the effects of the W compounds on these processes were further investigated. First, W-7 dose dependently diminished K+ (45 mm)-induced Ca2+ signals (IC50, ∼25 μm), and W-13 (100μ m) reduced the K+ (45 mm)-induced [Ca2+]i rise by about 40–6...