omega-agatoxin-iva and Pancreatic-Neoplasms

The high-voltage-activated (HVA) Ba2+ currents of rat insulinoma RINm5F cells insensitive to dihydropyridines (DHP) and omega-conotoxin GVIA (omega-CTx-GVIA) have been studied for their sensitivity to omega-agatoxin-IVA (omega-Aga-IVA) and omega-CTx-MVIIC. Blockade of HVA currents by omega-Aga-IVA was partial (mean 24%), reversible and saturated around 350 nM (half block approximately 60 nM). Blockade by omega-CTx-MVIIC was more potent (mean 45%), partly irreversible and saturated above 3 microM. The effects of both toxins were additive with that of nifedipine (5 microM) and were more pronounced at positive potentials. omega-Aga-IVA action was additive with that of omega-CTx-GVIA (3 microM) but was largely prevented by cell pre-treatment with omega-CTx-MVIIC (3 microM). In contrast, omega-CTx-MVIIC block was attenuated by omega-CTx-GVIA treatment (approximately 15%), suggesting that omega-CTx-MVIIC blocks the N-type (approximately 15%) and the non-L-, non-N-type channel sensitive to omega-Aga-IVA (approximately 30%). Consistent with this, cells deprived of most non-L-type channels by pre-incubation with omega-CTx-GVIA and omega-CTx-MVIIC exhibited predominant L-type currents that activated at more negative potentials than in normal cells (-30 mV in 5 mM Ba2+) and were effectively depressed by nifedipine (maximal block of 95% from -30 mV to +40 mV). Our results suggest that, besides L- and N-type channels, insulin-secreting RINm5F cells possess also a non-L-, non-N-type channel that contributes significantly to the total current (approximately 30%). Although the pharmacology of this channel is similar to Q-type and alpha 1 class A channels, its range of activation (> -20 mV) and its slow inactivation time course resemble more that of N- and P-type channels. The channel is therefore referred to as "Q-like".

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Electric Stimulation; Insulinoma; Kinetics; Nifedipine; omega-Agatoxin IVA; omega-Conotoxins; Pancreatic Neoplasms; Peptides; Rats; Spider Venoms; Tumor Cells, Cultured