Effects of SDPNFLRF-amide (PF1) on voltage-activated currents in Ascaris suum muscle

Helminth infections are of significant concern in veterinary and human medicine. The drugs available for chemotherapy are limited in number and the extensive use of these drugs has led to the development of resistance in parasites of animals and humans (Geerts and Gryseels, 2000; Kaplan, 2004; Osei-Atweneboana et al., 2007). The cyclooctadepsipeptide, emodepside, belongs to a new class of anthelmintic that has been released for animal use in recent years. Emodepside has been proposed to mimic the effects of the neuropeptide PF1 on membrane hyperpolarization and membrane conductance (Willson et al., 2003). We investigated the effects of PF1 on voltage-activated currents in Ascaris suum muscle cells. The whole cell voltage-clamp technique was employed to study these currents. Here we report two types of voltage-activated inward calcium currents: transient peak (I(peak)) and a steady-state (I(ss)). We found that 1microM PF1 inhibited the two calcium currents. The I(peak) decreased from -146nA to -99nA (P=0.0007) and the I(ss) decreased from -45nA to -12nA (P=0.002). We also found that PF1 in the presence of calcium increased the voltage-activated outward potassium current (from 521nA to 628nA (P=0.004)). The effect on the potassium current was abolished when calcium was removed and replaced with cobalt; it was also reduced at a higher concentration of PF1 (10microM). These studies demonstrate a mechanism by which PF1 decreases the excitability of the neuromuscular system by modulating calcium currents in nematodes. PF1 inhibits voltage-activated calcium currents and potentiates the voltage-activated calcium-dependent potassium current. The effect on a calcium-activated-potassium channel appears to be common to both PF1 and emodepside (Guest et al., 2007). It will be of interest to investigate the actions of emodepside on calcium currents to further elucidate the mechanism of action.