Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation.
TRPA1 is a nonselective cation channel belonging to the transient receptor potential (TRP) family that is expressed in peripheral sensory neurons and may play important roles in pain perception and inflammation. We found that agonist stimulation of TRPA1, along with other members of the TRP family (TRPV1-4 and TRPM8), can induce the appearance of a large pore permeable to large organic cations such as Yo-Pro (YP) and N-methyl-d-glucamine, in an agonist and divalent cation-dependent manner. YP uptake was not inhibited by a panel of putative gap junction/pannexin blockers, suggesting that gap junction proteins are not required in this process. Our data suggest that changes in the TRP channel selectivity filter itself result in a progressive but reversible pore dilation process, a process that is under strong regulation by external calcium ions. Our data suggest that calcium plays a novel role in setting the amount of time TRPA1 channels spend in a dilated state providing a mechanism that may limit sensory neuron activation by painful or irritating substances.
Banke
T G
TG
Johnson & Johnson PRD, LLC, Pain and Related Disorders, San Diego, CA 92121, USA. tbanke@gmail.com
Chaplan
S R
SR
Wickenden
A D
AD
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001583:Benzoxazoles / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D017879:Isothiocyanates / Q000494:pharmacology; D007700:Kinetics; D008536:Meglumine / Q000378:metabolism; D049990:Membrane Transport Modulators / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058910:Purinergic P2 Receptor Agonists; D011806:Quinolinium Compounds / Q000378:metabolism; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D012459:Salicylates / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000819:agonists / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists / Q000378:metabolism; D014162:Transfection; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D001583:Benzoxazoles; D015220:Calcium Channels; D002219:Carbamates; D017879:Isothiocyanates; D049990:Membrane Transport Modulators; D009419:Nerve Tissue Proteins; C546468:P2RX7 protein, human; D058910:Purinergic P2 Receptor Agonists; D011806:Quinolinium Compounds; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D012459:Salicylates; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; D050051:Transient Receptor Potential Channels; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C093323:farnesylthiosalicylic acid; C089813:YO-PRO 1; D005204:Farnesol; D008536:Meglumine; C004471:allyl isothiocyanate; D002118:Calcium