Pyrethroid action on calcium channels: neurotoxicological implications.
Actions of cismethrin versus deltamethrin were compared using two functional attributes of rat brain synaptosomes. Both pyrethroids increased calcium influx but only deltamethrin increased Ca(2+)-dependent neurotransmitter release following K(+)-stimulated depolarization. The action of deltamethrin was stereospecific, concentration-dependent, and blocked by omega-conotoxin GVIA. These findings delineate a separate action for deltamethrin and implicate N-type rat brain Ca(v)2.2 voltage-sensitive calcium channels (VSCC) as target sites that are consistent with the in vivo release of neurotransmitter caused by deltamethrin. Deltamethrin (10(-7) M) reduced the peak current (approx. -47%) of heterologously expressed wild type Ca(v)2.2 in a stereospecific manner. Mutation of threonine 422 to glutamic acid (T422E) in the alpha(1)-subunit results in a channel that functions as if it were permanently phosphorylated. Deltamethrin now increased peak current (approx. +49%) of T422E Ca(v)2.2 in a stereospecific manner. Collectively, these results substantiate that Ca(v)2.2 is directly modified by deltamethrin but the resulting perturbation is dependent upon the phosphorylation state of Ca(v)2.2. Our findings may provide a partial explanation for the different toxic syndromes produced by these structurally-distinct pyrethroids.
Clark
J Marshall
JM
Department of Veterinary and Animal Science, University of Massachusetts, Morrill 1 N311, 639 N. Pleasant St., Amherst, MA 01003, USA. jclark@vasci.umass.edu
Symington
Steven B
SB
D000818:Animals; D001921:Brain / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects*; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects; D009570:Nitriles / Q000633:toxicity*; D016805:Paramecium tetraurelia / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011722:Pyrethrins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology; D020866:omega-Conotoxin GVIA / Q000633:toxicity
D015220:Calcium Channels; D009570:Nitriles; D015221:Potassium Channels; D011722:Pyrethrins; C017180:decamethrin; D020866:omega-Conotoxin GVIA