Modulation of TRPC5 cation channels by halothane, chloroform and propofol.
OBJECTIVE
TRPC5 is a mammalian homologue of the Drosophila Transient Receptor Potential (TRP) channel and has expression and functions in the cardiovascular and nervous systems. It forms a calcium-permeable cation channel that can be activated by a variety of signals including carbachol (acting at muscarinic receptors), lanthanides (e.g. Gd3+) and phospholipids (e.g. lysophosphatidylcholine: LPC). Here we report the effects of inhalational (halothane and chloroform) and intravenous (propofol) general anaesthetics upon TRPC5.


METHODS
Human TRPC5 channels were expressed in HEK 293 cells and studied using fura-2 and patch-clamp recording to measure intracellular calcium and membrane currents respectively at room temperature. Human TRPM2 channels were studied for comparison.


RESULTS
TRPC5 activation by carbachol, Gd3+ or LPC was inhibited by halothane and chloroform at > or =0.1 and 0.2 mM respectively. Neither agent inhibited TRPM2. Propofol had an initial stimulatory effect on TRPC5 (evident in patch-clamp recordings only) and an inhibitory effect at > or =10 microM. TRPM2 was not affected by propofol. Propofol inhibited activation of TRPC5 by Gd3+ but not LPC, suggesting the effect was not directly on the channel. Propofol's anti-oxidant property was not necessary for its inhibitory effect because di-isopropyl benzene, a propofol analogue that lacks the hydroxyl group, also inhibited TRPC5.


CONCLUSIONS
The data show the sensitivity of TRPC5 channel to general anaesthetics and suggest that some of the effects could have clinical relevance. The effects may be explained in part by the sensitivity of the channel to biophysical properties of the lipid bilayer.
Bahnasi
Y M
YM
Faculty of Biological Sciences, Institute of Membrane and Systems Biology, University of Leeds, Leeds, UK.
Wright
H M
HM
Milligan
C J
CJ
Dedman
A M
AM
Zeng
F
F
Hopkins
P M
PM
Bateson
A N
AN
Beech
D J
DJ
D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002725:Chloroform / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D016257:Fura-2; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D028581:Lanthanoid Series Elements / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000187:drug effects* / Q000378:metabolism; D050053:TRPM Cation Channels / Q000187:drug effects / Q000378:metabolism
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D005456:Fluorescent Dyes; D028581:Lanthanoid Series Elements; D008244:Lysophosphatidylcholines; D050052:TRPC Cation Channels; C491780:TRPC5 protein, human; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D002725:Chloroform; D002118:Calcium; D016257:Fura-2; D006221:Halothane; D015742:Propofol