The phosphatidylinositol 4-kinase inhibitor phenylarsine oxide blocks evoked neurotransmitter release by reducing calcium entry through N-type calcium channels.
The effects of the phosphatidylinositol 4-kinase inhibitor, phenylarsine oxide (PAO), on acetylcholine (ACh) release and on prejunctional Ca(2+) currents were studied at the frog neuromuscular junction using electrophysiological recording techniques. Application of PAO (30 microM) increased both spontaneous ACh release reflected as miniature end-plate potential (mepp) frequencies and evoked ACh release reflected as end-plate potential (epp) amplitudes with a similar time course. Following the initial increase in epp amplitudes produced by PAO, epps slowly declined and were eventually abolished after approximately 20 min. However, mepp frequencies remained elevated over this time period. PAO (30 microM) also inhibited the perineural voltage change associated with Ca(2+) currents through N-type Ca(2+) channels (prejunctional Ca(2+) currents) at motor nerve endings. Addition of British anti-lewisite (BAL, 1 mM), an inactivator of PAO, partially reversed both the inhibition of epps and the inhibition of the prejunctional Ca(2+) current. The effects of PAO on N-type Ca(2+) channels were investigated more directly using the whole cell patch clamp technique on acutely dissociated sympathetic neurons. Application of PAO (30 - 40 microM) to these neurons decreased the voltage-activated calcium currents through N-type Ca(2+) channels, an effect that was partially reversible by BAL. In combination, these results suggest that inhibition of neurotransmitter release by PAO occurs as a consequence of the inhibition of Ca(2+) entry via N-type calcium channels. The relationship between the effects of PAO on N-type Ca(2+) channels in motor nerve endings and in neuronal soma is discussed.
Searl
T J
TJ
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois, IL 60611, USA.
Silinsky
E M
EM
D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D004112:Dimercaprol / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011894:Rana pipiens
D001152:Arsenicals; D020864:Calcium Channels, N-Type; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D004112:Dimercaprol; C029341:oxophenylarsine; D019870:1-Phosphatidylinositol 4-Kinase; D002118:Calcium