title: Involvement of TRP channels in the CO₂ chemosensitivity of locus coeruleus neurons.
abstract: 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.
authors: Department of Biology, Georgia State University, Atlanta, GA 30302, USA.
authors: Ningren
authors: N
authors: Cui
authors: Xiaoli
authors: X
authors: Zhang
authors: Jyothirmayee S
authors: JS
authors: Tadepalli
authors: Lei
authors: L
authors: Yu
authors: Hongyu
authors: H
authors: Gai
authors: James
authors: J
authors: Petit
authors: Ravi T
authors: RT
authors: Pamulapati
authors: Xin
authors: X
authors: Jin
authors: Chun
authors: C
authors: Jiang
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002245:Carbon Dioxide / Q000378:metabolism / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006935:Hypercapnia / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010852:Picrotoxin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D002121:Calcium Channel Blockers; D002245:Carbon Dioxide; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D007093:Imidazoles; D010852:Picrotoxin; D012333:RNA, Messenger; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; C112021:Trpc5 protein, mouse; C421903:Trpm7 protein, mouse; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole