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Modulation of KCNQ Channels is a Potential Mechanism for Controlling Inspiratory Burst Duration
Author(s) -
Revill Ann L,
Katzell Alexis,
Funk Gregory D
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.729.6
Subject(s) - depolarization , membrane potential , chemistry , bursting , brainstem , biophysics , electrophysiology , medicine , neuroscience , biology
The preBötzinger Complex (preBötC) is a key site of inspiratory rhythm generation in mammals and significant progress has been made toward defining the mechanisms underlying inspiratory burst generation. In contrast, the mechanisms that control burst duration have received relatively little attention. Here we test the hypotheses that KCNQ channels help determine inspiratory burst duration and contribute to burst termination. KCNQ channels mediate a slow, voltage‐gated outward K + current that is active at resting membrane potential and becomes larger with membrane depolarization. This current helps determine resting membrane potential and also acts to stabilize membrane potential. Using rhythmically‐active brainstem spinal cord (BSSC) and rhythmic medullary slice preparations from neonatal rats (postnatal day 0–4), we examined the role of KCNQ in controlling inspiratory behavior by assessing the effects of KCNQ inhibitors and activators on inspiratory burst duration and inspiratory frequency recorded from the C4 ventral nerve root in BSSC preparations and the XII nerve in slices. Bath application of the KCNQ channel blockers XE991 (0.1 μM and 1 μM) and linopirdine (6 μM, BSSC; 3 μM, slice) caused a time‐ and concentration‐dependent increase in burst duration (XE991, 1 μM: BSSC: 1.35 ± 0.05 fold increase, n = 6, p < 0.05; slice: 3.59 ± 0.20 fold increase, n = 5, p < 0.05; linopirdine: BSSC: 1.22 ± 0.04 fold increase, n = 8, p < 0.05 slice: 1.94 ± 0.13 fold increase, n = 6, p < 0.05), but only XE991 caused a decrease in burst frequency (1 μM: 0.52 ± 0.03 of control levels, p < 0.05). Local microinjection of XE991 (10 μM) directly into the preBötC produced very similar effects on burst duration (3.65 ± 0.86 fold increase, n = 3, p < 0.05) and burst frequency (0.59 ± 0.04 of control, p < 0.05). In contrast, potentiation of the KCNQ current via bath application of retigabine (2 μM) caused a significant decrease in inspiratory burst duration (BSSC: 0.62 ± 0.05 times control, n = 5, p < 0.05; slice: 0.72 ± 0.06 times control, n = 8, p < 0.05) and a decrease in burst frequency. Inspiratory burst generation ceased when retigabine concentration was increased to 3 μM. These data suggest that activation of KCNQ channels specifically within the preBötC contributes to inspiratory burst termination and that their modulation may provide a mechanism for controlling inspiratory burst duration. Funding: CIHR, NSERC, WCHRI, AIHS, CFI. Support or Funding Information CIHR, NSERC, WCHRI, AIHS, CFI