title: Allethrin differentially modulates voltage-gated calcium channel subtypes in rat PC12 cells.
abstract: Pyrethroid insecticides are one of the most widely used classes of insecticides. Previous studies revealed that pyrethroids potently affect the insect voltage-gated sodium (Na(+)) channel (VGSC), resulting in prolonged channel open time. However, recent findings have suggested that pyrethroids may affect targets other than the VGSC. In particular, several studies have shown that pyrethroids can modulate the activity of voltage-gated calcium (Ca(2+)) channels (VGCCs). However, these studies often reported conflicting results; some studies observed stimulatory effects, whereas others observed inhibitory effects of pyrethroids on VGCCs. This study investigated whether allethrin (AL), a well-characterized type I pyrethroid, altered VGCC characteristics measured by whole-cell recording in rat pheochromocytoma cells (PC12) differentiated with nerve growth factor (NGF). AL (5 microM) increased peak, end, and tail composite VGCC current independent of its effects on VGSCs. After blocking VGCC subtype-specific current with omega-conotoxin GVIA (GVIA, an N-type VGCC antagonist) or nimodipine (NIM, an L-type VGCC antagonist), our data further suggest that AL differentially affects VGCC subtypes. Thus, AL apparently stimulated GVIA-insensitive current while inhibiting NIM-insensitive current. AL also significantly altered the voltage dependency of activation and inactivation of L-type VGCCs. The differential modulation of VGCC subtypes by AL may explain some of the conflicting observations of other studies.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824-1317, USA.
authors.forename: April P
authors.initials: AP
authors.lastname: Neal
authors.forename: Yukun
authors.initials: Y
authors.lastname: Yuan
authors.forename: William D
authors.initials: WD
authors.lastname: Atchison
mesh_terms: D000487:Allethrins / Q000633:toxicity*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000145:classification / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D013779:Tetrodotoxin / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D000487:Allethrins; D020746:Calcium Channels, L-Type; D007306:Insecticides; D013779:Tetrodotoxin; D020866:omega-Conotoxin GVIA
references.citation: Neurotoxicology. 2006 Jul;27(4):594-603
references.pmid: 16678264
references.citation: Pest Manag Sci. 2008 Jun;64(6):628-38
references.pmid: 18383452
references.citation: Sci Total Environ. 2010 Feb 1;408(5):1145-53
references.pmid: 19896164
references.citation: Ann N Y Acad Sci. 1986;479:133-51
references.pmid: 2433987
references.citation: Brain Res. 1999 Nov 13;847(1):38-49
references.pmid: 10564734
references.citation: Environ Res. 2009 Jan;109(1):116-22
references.pmid: 19019354
references.citation: J Pharmacol Exp Ther. 2004 Mar;308(3):805-13
references.pmid: 14634047
references.citation: J Neurosci. 1996 Dec 1;16(23):7557-65
references.pmid: 8922412
references.citation: J Pharmacol Exp Ther. 1994 Aug;270(2):595-603
references.pmid: 8071852
references.citation: Brain Res. 1994 May 9;645(1-2):318-24
references.pmid: 8062093
references.citation: Nature. 1997 Jan 30;385(6615):442-6
references.pmid: 9009192
references.citation: Neurotoxicology. 2000 Feb-Apr;21(1-2):37-47
references.pmid: 10794383
references.citation: Toxicol Appl Pharmacol. 2008 Sep 15;231(3):273-81
references.pmid: 18538810
references.citation: Toxicol Appl Pharmacol. 2004 Apr 15;196(2):303-18
references.pmid: 15081275
references.citation: Neurochem Int. 2002 Dec;41(6):391-7
references.pmid: 12213226
references.citation: Biophys J. 2003 May;84(5):3007-21
references.pmid: 12719232
references.citation: Toxicon. 2007 Feb;49(2):124-41
references.pmid: 17239913
references.citation: Environ Health Perspect. 2005 Feb;113(2):123-36
references.pmid: 15687048
references.citation: J Biol Chem. 2003 Jun 20;278(25):22316-24
references.pmid: 12679337
references.citation: J Pharmacol Exp Ther. 1972 Sep;182(3):442-53
references.pmid: 4341317
references.citation: Toxicol Lett. 1998 Nov 12;99(3):207-21
references.pmid: 9862287
references.citation: J Neurosci. 1989 Nov;9(11):3976-87
references.pmid: 2479727
references.citation: Trends Neurosci. 2003 Dec;26(12):683-7
references.pmid: 14624853
references.citation: Arch Environ Contam Toxicol. 2010 May;58(4):908-17
references.pmid: 20016886
references.citation: Neuron. 1994 Dec;13(6):1433-8
references.pmid: 7993634
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10576-80
references.pmid: 7524096
references.citation: J Pharmacol Exp Ther. 2005 Dec;315(3):1109-18
references.pmid: 16109744
references.citation: Pest Manag Sci. 2001 Oct;57(10):877-88
references.pmid: 11695180
references.citation: Pharmacol Ther. 2006 Jul;111(1):174-93
references.pmid: 16324748
references.citation: J Med Toxicol. 2007 Sep;3(3):94-9
references.pmid: 18072143
references.citation: Neurotoxicology. 1991 Fall;12(3):473-92
references.pmid: 1720882