Involvement of TRP channels in the CO₂ chemosensitivity of locus coeruleus neurons

J Neurophysiol. 2011 Jun;105(6):2791-801. doi: 10.1152/jn.00759.2010. Epub 2011 Mar 23.


Catecholaminergic neurons in the locus coeruleus (LC) play a role in the ventilatory response to hypercapnia. Here, we show evidence for the involvement of transient receptor potential (TRP) channels. We found that the input resistance was reduced during an exposure to 8% CO(2) in ~35% LC neurons in mouse brain slices, accompanied by depolarization and higher firing activity. The neuronal responses suggest the opening of Na(+) or nonselective cationic channels instead of the closure of K(+) channels. As a major group of cationic channels, the TRP channels are expressed in the brain, some of which are activated by acidic pH. We therefore screened all representative TRP channels using the quantitative real-time PCR analysis. High levels of mRNA expression of TRPC5, TRPM2, and TRPM7 were found in the LC tissue. Of them, the TRPC5 transcript was the most abundant. The TRPC5 channel was activated by extracellular acidification when expressed in human embryonic kidney (HEK) cells. The TRPC5 currents started to be activated at pH 7.4 with pKa 6.9. The TRPC5 currents were also activated by isohydric hypercapnic and intracellular acidosis in a Ca(2+)-dependent manner. Consistently, the LC neurons were stimulated by both extra- and intracellular acidosis. The stimulatory effect of hypercapnia on LC neurons was eliminated by selective TRPC inhibitor SKF-96365 with and without the blockade of synaptic transmission. Single-cell PCR analysis indicated that TRPC5 mRNAs existed in the LC neurons. Thus these results strongly suggest that the TRP channels are likely to play a role in the CO(2) chemosensitivity of LC neurons, especially TRPC5.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Calcium Channel Blockers / pharmacology
  • Carbon Dioxide / metabolism
  • Carbon Dioxide / pharmacology*
  • Electric Stimulation / methods
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA Antagonists / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Hypercapnia / metabolism
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Locus Coeruleus / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects*
  • Patch-Clamp Techniques / methods
  • Picrotoxin / pharmacology
  • RNA, Messenger / metabolism
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / metabolism*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism
  • Transfection / methods


  • Calcium Channel Blockers
  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • Imidazoles
  • RNA, Messenger
  • TRPC Cation Channels
  • TRPM Cation Channels
  • TRPM2 protein, mouse
  • Trpc5 protein, mouse
  • Picrotoxin
  • Carbon Dioxide
  • Trpm7 protein, mouse
  • 1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole