| Full text | |
| Author(s): |
Sobrinho, Cleyton R.
[1]
;
Kuo, Fu-Shan
[2]
;
Barna, Barbara F.
[1]
;
Moreira, Thiago S.
[1]
;
Mulkey, Daniel K.
[2]
Total Authors: 5
|
| Affiliation: | [1] Univ Sao Paulo, Dept Physiol & Biophys, Sao Paulo - Brazil
[2] Univ Connecticut, Dept Physiol & Neurobiol, Pharm Bldg, Rm216, 75 North Eagleville Rd, Unit 3156, Storrs, CT 06269 - USA
Total Affiliations: 2
|
| Document type: | Journal article |
| Source: | JOURNAL OF PHYSIOLOGY-LONDON; v. 594, n. 2, p. 407-419, JAN 15 2016. |
| Web of Science Citations: | 5 |
| Abstract | |
ACh has long been considered important for the CO2/H+-dependent drive to breathe produced by chemosensitive neurons in the retrotrapezoid nucleus (RTN). However, despite this potentially important physiological role, almost nothing is known about the mechanisms responsible for the cholinergic control of RTN function. In the present study, we used slice-patch electrophysiology and pharmacological tools to characterize the effects of ACh on baseline activity and CO2/H+-sensitivity of RTN chemoreceptors, as well as to dissect the signalling pathway by which ACh activates these neurons. We found that ACh activates RTN chemoreceptors in a dose-dependent manner (EC50=1.2 mu m). The firing response of RTN chemoreceptors to ACh was mimicked by a muscarinic receptor agonist (oxotremorine; 1m), and blunted by M1- (pirezenpine; 2 mu m) and M3- (diphenyl-acetoxy-N-methyl-piperidine; 100 nm) receptor blockers, but not by a nicotinic-receptor blocker (mecamylamine; 10 mu m). Furthermore, pirenzepine, diphenyl-acetoxy-N-methyl-piperidine and mecamylamine had no measurable effect on the CO2/H+-sensitivity of RTN chemoreceptors. The effects of ACh on RTN chemoreceptor activity were also blunted by inhibition of inositol 1,4,5-trisphosphate receptors with 2-aminoethoxydiphenyl borate (100 mu m), depletion of intracellular Ca2+ stores with thapsigargin (10 mu m), inhibition of casein kinase 2 (4,5,6,7-tetrabromobenzotriazole; 10 mu m) and blockade of KCNQ channels (XE991; 10 mu m). These results show that ACh activates RTN chemoreceptors by a CO2/H+ independent mechanism involving M1/M3 receptor-mediated inositol 1,4,5-trisphosphate/Ca+2 signalling and downstream inhibition of KCNQ channels. Identifying the components of the signalling pathway coupling muscarinic receptor activation to changes in chemoreceptor activity may provide new potential therapeutic targets for the treatment of respiratory control disorders. (AU) | |
| FAPESP's process: | 09/54888-7 - Neural mechanisms involved on chemoreception |
| Grantee: | Eduardo Colombari |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 13/10573-8 - Ventral surface chemoreceptor neuronal mechanisms |
| Grantee: | Thiago dos Santos Moreira |
| Support Opportunities: | Regular Research Grants |