Phosphoinositide modulation of heteromeric Kv1 channels adjusts output of spiral ganglion neurons from hearing mice

Spiral ganglion neurons (SGNs) relay acoustic code from cochlear hair cells to the brainstem, and their stimulation enables electrical hearing via cochlear implants. Rapid adaptation, a mechanism that preserves temporal precision, and a prominent feature of auditory neurons, is regulated via dendrotoxin-sensitive low-threshold voltage-activated (LVA) K⁺ channels. Here, we investigated the molecular physiology of LVA currents in SGNs cultured from mice following the onset of hearing (postnatal days 12-21). Kv1.1- and Kv1.2-specific toxins blocked the LVA currents in a comparable manner, suggesting that both subunits contribute to functional heteromeric channels. Confocal immunofluorescence in fixed cochlear sections localized both Kv1.1 and Kv1.2 subunits to specific neuronal microdomains, including the somatic membrane, juxtaparanodes, and the first heminode, which forms the spike initiation site of the auditory nerve. The spatial distribution of Kv1 immunofluorescence appeared mutually exclusive to that of Kv3.1b subunits, which mediate high-threshold voltage-activated currents. As Kv1.2-containing channels are positively modulated by membrane phosphoinositides, we investigated the influence of phosphatidylinositol-4,5-bisphosphate (PIP₂) availability on SGN electrophysiology. Reducing PIP₂ production using wortmannin, or sequestration of PIP₂ using a palmitoylated peptide (PIP₂-PP), slowed adaptation rate in SGN populations. PIP₂-PP specifically inhibited the LVA current in SGNs, an effect reduced by intracellular dialysis of a nonhydrolysable analog of PIP₂. PIP₂-PP also inhibited heterologously expressed Kv1.1/Kv1.2 channels, recapitulating its effect in SGNs. Collectively, the data identify Kv1.1/Kv1.2 heteromeric channels as key regulators of action potential initiation and propagation in the auditory nerve, and suggest that modulation of these channels by endogenous phosphoinositides provides local control of membrane excitability. SIGNIFICANCE STATEMENT: Rapid spike adaptation is an important feature of auditory neurons that preserves temporal precision. In spiral ganglion neurons, the primary afferents in the cochlea, adaptation is regulated by heteromeric ion channels composed of Kv1.1 and Kv1.2 subunits. These subunits colocalize to common functional microdomains, such as juxtaparanodes and the somatic membrane. Activity of the heteromeric channels is controlled by cellular availability of PIP₂, a membrane phospholipid. This mechanism provides an intrinsic regulation of output from the auditory nerve, which could be targeted for therapeutic adjustment of hearing sensitivity.12 page(s

A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

C-type natriuretic peptide (CNP) is involved in the regulation of vascular homeostasis, which is at least partly mediated through agonism of natriuretic peptide receptor C (NPR-C), and loss of this signaling has been associated with vascular dysfunction. As such, NPR-C is a novel therapeutic target to treat cardiovascular diseases. A series of novel small molecules have been designed and synthesized, and their structure-activity relationships were evaluated by a surface plasmon resonance binding assay. The biological activity of hit compounds was confirmed through organ bath assays measuring vascular relaxation and inhibition of cAMP production, which was shown to be linked to its NPR-C activity. Lead compound 1 was identified as a potent agonist (EC50 ∼ 1 μM) with promising in vivo pharmacokinetic properties