Selective KCNQ2/3 Potassium Channel Opener ICA069673 Inhibits Excitability in Mouse Vagal Sensory Neurons

Abstract

The excitability of vagal sensory neurons is abnormally enhanced in inflammatory visceral diseases, contributing to the unproductive and diffcult-to-treat neuronally based symptoms such as non-cardiac chest pain and excessive coughing. Identification of targets and modulators capable of regulating the excitability of vagal sensory neurons may lead to novel therapeutic options. The KCNQ/KV7/M-channel is increasingly recognized as an intrinsic regulator of excitability in neurons, and several neuronal KCNQ2/3-selective M-channel openers have been developed. This study aimed to characterize the effects of one of these KCNQ2/3-selective activators, ICA-069673, on the M-current (IM) in mouse nodose neurons, and to determine its effects on excitability and action potential firings using perforated patch-clamp technique. The results showed that ICA-069673 enhanced IM density, accelerated the activation and delayed the deactivation of M-channels in a concentration-dependent manner. The EC50 of ICA-069673 in enhancing IM determined at -30 mV is 0.52 μM. ICA-069673 at 10 μM shifted the voltage-dependent activation of IM in hyperpolarizing direction by -25.5 ± 4.1 mV (p<0.001) and increased the maximal conductance from 8.1 ± 4.0 to 12.6±7.4 nS/pF (p=0.031). In a total of 48 nodose neurons studied on voltage-clamp mode, ICA-069673 enhanced IM in 41 neurons (~85%). Consistent with its effects on IM, 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. These results indicate that opening KCNQ2/3-mediated M-channels is suffcient to suppress the excitability and enhance spike accommodation in vagal sensory neurons, and provide evidence supporting further investigation into the effcacy of ICA-069673 in normalizing the aberrant vagal visceral nociception. The study is supported by NIH Grant R35HL155671. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.