TRPA1 channels: novel targets of 1,4-dihydropyridines.
Transient receptor potential type A1 (TRPA1) channels are cation permeable channels activated by irritant chemicals and pungent natural compounds. Their location in peptidergic sensory terminals innervating the skin and blood vessels makes them important effectors of vasodilator responses of neural origin. 1,4-dihydropyridines are a class of L-type calcium channel antagonists commonly used in the treatment of hypertension and ischemic heart disease. Here we show that four different 1,4-dihydropyridines (nifedipine, nimodipine, nicardipine and nitrendipine), and the structurally related L-type calcium channel agonist BayK8644, exert powerful excitatory effects on TRPA1 channels. The activation does not depend on elevated Ca2+ levels and cross-desensitizes with that produced by other TRPA1 agonists. The activation produced by nifedipine was reduced by camphor and the selective TRPA1 antagonist HC03001. In a subclass of mouse nociceptors expressing TRPA1 channels, assessed by responses to the TRPA1 agonist mustard oil, nifedipine also produced large elevations in [Ca2+](i). These responses were fully abrogated in TRPA1(-/-) mice. These findings identify TRPA1 channels as a new molecular target for the 1,4-dihydropyridine class of calcium channel modulators.
Fajardo
Otto
O
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Alicante, Spain.
Meseguer
Victor
V
Belmonte
Carlos
C
Viana
Félix
F
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines / Q000494:pharmacology*; D016503:Drug Delivery Systems; D051379:Mice; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors*; D014664:Vasodilation
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D002118:Calcium