Selective KCNQ2/3 Potassium Channel Opener ICA-069673 Inhibits Excitability in Mouse Vagal Sensory Neurons

Heightened excitability of vagal sensory neurons in inflammatory visceral diseases contributes to unproductive and difficult-to-treat neuronally based symptoms such as visceral pain and dysfunction. Identification of targets and modulators capable of regulating the excitability of vagal sensory neurons may lead to novel therapeutic options. KCNQ1–KCNQ5 genes encode K_V7.1-7.5 potassium channel α-subunits. Homotetrameric or heterotetrameric K_V7.2-7.5 channels can generate the so-called M-current (I_M) known to decrease the excitability of neurons including visceral sensory neurons. This study aimed to address the hypothesis that K_V7.2/7.3 channels are key regulators of vagal sensory neuron excitability by evaluating the effects of KCNQ2/3-selective activator, ICA-069673, on I_M in mouse nodose neurons and determining its effects on excitability and action potential firings using patch clamp technique. The results showed that ICA-069673 enhanced I_M density, accelerated the activation, and delayed the deactivation of M-channels in a concentration-dependent manner. ICA-069673 negatively shifted the voltage-dependent activation of I_M and increased the maximal conductance. Consistent with its effects on I_M, ICA-069673 induced a marked hyperpolarization of resting potential and reduced the input resistance. The hyperpolarizing effect was more pronounced in partially depolarized neurons. Moreover, ICA-069673 caused a 3-fold increase in the minimal amount of depolarizing current needed to evoke an action potential, and significantly limited the action potential firings in response to sustained suprathreshold stimulations. ICA-069673 had no effect on membrane currents when Kcnq2 and Kcnq3 were deleted. These results indicate that opening KCNQ2/3-mediated M-channels is sufficient to suppress the excitability and enhance spike accommodation in vagal visceral sensory neurons.

SIGNIFICANCE STATEMENT

This study supports the hypothesis that selectively activating KCNQ2/3-mediated M-channels is sufficient to suppress the excitability and action potential firings in vagal sensory neurons. These results provide evidence in support of further investigations into the treatment of various visceral disorders that involve nociceptor hyperexcitability with selective KCNQ2/3 M-channel openers.