Mechanisms of eosinophil major basic protein-induced hyperexcitability of vagal pulmonary chemosensitive neurons.
We have reported recently that eosinophil-derived basic proteins directly enhance the capsaicin- and electrical stimulation-evoked whole cell responses in rat pulmonary sensory neurons (19). Our present study further elucidates the mechanisms underlying the sensitization of pulmonary afferent nerves induced by these cationic proteins. Our results show that pretreatment with eosinophil major basic protein (MBP; 2 microM, 60 s) significantly enhanced the excitability of isolated rat vagal pulmonary chemosensitive neurons to acid and ATP in the current-clamp mode, but this potentiating effect was absent in the voltage-clamp recordings. The hyperexcitability induced by MBP was not prevented by the blockade of either transient receptor potential vanilloid type-1 receptor (TRPV1) selectively (inhibitor: AMG 9810; 1 microM, 2 min) or all TRPV1-4 channels (inhibitor: ruthenium red; 5 microM, 2 min). In addition, MBP also markedly potentiated the excitability of mouse pulmonary chemosensitive neurons, and no detectable difference was found between those isolated from wild-type and TRPV1 knockout mice. Furthermore, MBP pretreatment affected the decay time and recovery phase of the action potentials evoked by current injections and significantly inhibited both the sustained delayed-rectifier voltage-gated K(+) current (IK(dr)) and the A-type, fast-inactivating K(+) current (IK(a)) in these sensory neurons. In conclusion, our results indicate that the inhibition of IK(dr) and IK(a) should, at least in part, account for the hyperexcitability of pulmonary chemosensitive neurons induced by eosinophil-derived cationic proteins, whereas an interaction with TRPV1 channels does not seem to be required for the sensitizing effect of these proteins.
Gu
Qihai
Q
Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky 40536-0298, USA.
Lim
Michelle E
ME
Gleich
Gerald J
GJ
Lee
Lu-Yuan
LY
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D047093:Eosinophil Major Basic Protein / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000294:innervation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D050916:TRPV Cation Channels / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014630:Vagus Nerve / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
D024642:Potassium Channels, Voltage-Gated; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; D047093:Eosinophil Major Basic Protein