Abstract
KCNQ (Kv7) channels underlie a voltage-gated K+ current best known for control of neuronal excitability, and its inhibition by Gq/11-coupled, muscarinic signaling. Studies have indicated expression of KCNQ channels in airway smooth muscle (ASM), a tissue that is predominantly regulated by muscarinic receptor signaling. Therefore, we investigated the function of KCNQ channels in rodent ASM and their interplay with Gq/11-coupled M3 muscarinic receptors. Perforated-patch clamp of dissociated ASM cells detected a K+ current inhibited by the KCNQ antagonist, XE991, and augmented by the specific agonist, flupirtine. KCNQ channels begin to activate at voltages near resting potentials for ASM cells, and indeed XE991 depolarized resting membrane potentials. Muscarinic receptor activation inhibited KCNQ current weakly (~20%) at concentrations half-maximal for contractions. Thus, we were surprised to see that KCNQ had no affect on membrane voltage or muscle contractility following muscarinic activation. Further, M3 receptor-specific antagonist J104129 fumarate alone did not reveal KCNQ effects on muscarinic evoked depolarization or contractility. However, a role for KCNQ channels was revealed when BK-K+ channel activities are reduced. While KCNQ channels do control resting potentials, they appear to play a redundant role with BK calcium-activated K+ channels during ASM muscarinic signaling. In contrast to effect of antagonist, we observe that KCNQ agonist flupirtine caused a significant hyperpolarization and reduced contraction in vitro irrespective of muscarinic activation. Using non-invasive whole animal plethysmography, the clinically approved KCNQ agonist retigabine caused a transient reduction in indexes of airway resistance in both wild type and BK β1 knockout (KO) mice treated with the muscarinic agonist. These findings indicate that KCNQ channels can be recruited via agonists to oppose muscarinic evoked contractions and may be of therapeutic value as bronchodilators.
Highlights
The control of membrane voltage by K+ channels serves as a negative feedback to oppose voltage-dependent calcium influx pathways that contribute to airway smooth muscle (ASM) contraction
Do KCNQ channels have redundant function with the more established ASM K+ channel, the BK channel, or do the two types of K+ channels work in parallel? In this study, we investigate the role of KCNQ channels in mouse and rat tracheal smooth muscle (TSM)
A major observation of this study is that KCNQ channels control resting membrane potential of ASM, which is consistent with their activation at relatively negative (> −40 mV) membrane potentials
Summary
The control of membrane voltage by K+ channels serves as a negative feedback to oppose voltage-dependent calcium influx pathways that contribute to airway smooth muscle (ASM) contraction. Channels in control of contraction of various smooth muscle cell types (Greenwood and Ohya, 2009; Gurney et al, 2010), including guinea pig and human ASM (Brueggemann et al, 2012). Recent studies suggest that KCNQ1,4, and 5 are the predominant subunits in smooth muscle (Greenwood and Ohya, 2009). Robust expression of KCNQ channels composed of KCNQ1,4,5 subunits has been documented in vascular smooth muscle, in which they, like BK channels, play a prominent role in controlling contraction Mackie and Byron, 2008; Greenwood and Ohya, 2009). In addition to vascular smooth muscle, KCNQ channels moderate constriction of bladder, myometrium, and gut smooth muscle
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