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Heteromeric Kv1.2 channels counteract persistent sodium currents in proprioceptive DRG neurons

ABSTRACT: Voltage-gated potassium channels (VGKCs) comprise one of the largest, most diverse and complex families of ion channels. Approximately 70 genes encode the alpha subunits that form homomeric VGKC channels. In addition, these subunits can form functional heteromeric channels, thus exponentially increasing the diversity of VGKCs. The functional expression and physiological role of heteromeric K-channels have remained largely unexplored due to the lack of tools to probe their functions. Conotoxins have high affinity and specificity for heteromeric combinations of K-channels and show great promise for elucidating their functions. In this work, using conotoxin kM-RIIIJ as a pharmacological probe, we explore the expression and physiological functions of heteromeric Kv1.2 channels using constellation pharmacology. We report that heteromers of Kv1.2/1.1 are highly expressed in proprioceptive neurons found in the dorsal root ganglion (DRG). Inhibition of Kv1.2/1.1 heteromers leads to an influx of calcium ions, suggesting that these channels regulate neuronal excitability. We also present evidence that Kv1.2/1.1 heteromers counteract persistent sodium currents, and that inhibiting these channels leads to tonic firing of action potentials. Additionally, kM-RIIIJ induces impaired proprioception in mice, uncovering a previously unrecognized physiological role of heteromeric Kv1.2/1.1 channels in proprioceptive sensory neurons of the DRG.

ORGANISM(S): Mus musculus

PROVIDER: GSE279047 | GEO | 2025/01/02

REPOSITORIES: GEO

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Project description:Vagal afferent neurons are thought to convey primarily physiological information, whereas spinal afferents transmit noxious signals from the viscera to the central nervous system. In order to elucidate molecular identities for these different properties, we compared gene expression profiles of neurons located in nodose ganglia (NG) and dorsal root ganglia (DRG) in mice. Intraperitoneal administration of Alexa Fluor-488 conjugated Cholera toxin B allowed identification of neurons projecting to the viscera. Fluorescent neurons in DRG (from T10 to T13) and NG were isolated using laser capture microdissection. Gene expression profiles of visceral afferent neurons, obtained by microarray hybridization, were analysed using multivariate spectral map analysis, SAM algorithm (Significance Analysis of Microarray data) and fold-difference filtering. A total of 1996 genes were found to be differentially expressed in DRG versus NG, including 41 G-protein coupled receptors and 60 ion channels. Expression profiles obtained on laser-captured neurons were contrasted to those obtained on whole ganglia demonstrating striking differences and the need for microdissection when studying visceral sensory neurons because of dilution of the signal by somatic sensory neurons. Furthermore, a detailed catalogue of all adrenergic and cholinergic, GABA, glutamate, serotonin and dopamine receptors, voltage-gated potassium, sodium and calcium channels and transient receptor potential cation channels present in visceral afferents is provided. Our genome-wide expression profiling data provide novel insight into molecular signatures that underlie both functional differences and similarities between NG and DRG visceral sensory neurons. Moreover, these findings will offer novel insight into mode of action of pharmacologic agents modulating visceral sensation. Experiment Overall Design: Three separate experiments were performed. First, 5 whole dorsal root ganglia were compared to 7 whole nodose ganglia. Second, Laser captured visceral neurons derived from 5 dorsal root ganglia and 5 nodose ganglia were compared on MG-U74Av2. Third, Laser captured visceral neurons derived from 9 dorsal root ganglia and 11 nodose ganglia were compared on Mouse430_2.

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Heteromeric Kv1.2 channels counteract persistent sodium currents in proprioceptive DRG neurons

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