Kv2.1

Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD...

The voltage gated (Kv) slow-inactivating delayed rectifier channel regulates the development of hollow organs of the zebrafish. The functional channel consists of the tetramer of electrically active Kcnb1 (Kv2.1) subunits and Kcng4b (Kv6.4) modulatory or electrically silent subunits. The two mutations in zebrafish kcng4b gene - kcng4b-C1 and kcng4b-C2 (Gasanov et al., 2021) - have been studied during ear development using electrophysiology, developmental biology and in silico structural modelling. kcng4b-C1 mutation causes a C-terminal truncation characterized by mild Kcng4b loss-of-function (LOF) manifested by failure of kinocilia to extend and formation of ectopic otoliths...

Sertraline is a commonly used antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class. In this study, we have used the patch-clamp technique to assess the effects of sertraline on Kv2.1 channels heterologously expressed in HEK-293 cells and on the voltage-gated potassium currents (IKv ) of Neuro 2a cells, which are predominantly mediated by Kv2.1 channels. Our results reveal that sertraline inhibits Kv2.1 channels in a concentration-dependent manner. The sertraline-induced inhibition was not voltage-dependent and did not require the channels to be open...

Introduction: Astrocytic GLT-1 glutamate transporters ensure the fidelity of glutamic neurotransmission by spatially and temporally limiting glutamate signals. The ability to limit neuronal hyperactivity relies on the localization and diffusion of GLT-1 on the astrocytic surface, however, little is known about the underlying mechanisms. We show that two isoforms of GLT-1, GLT-1a and GLT-1b, form nanoclusters on the surface of transfected astrocytes and HEK-293 cells. Methods: We used both fixed and live cell super-resolution imaging of fluorescent protein and epitope tagged proteins in co-cultures of rat astrocytes and neurons...

In humans, Type 2 Diabetes Mellitus (T2DM) shows a higher prevalence in men compared to women, phenotype that has been attributed to a lower peripheral insulin sensitivity in men. Whether sex-specific differences in pancreatic β-cell function also contribute is largely unknown. Here we characterized the electrophysiological properties of β-cells in intact mouse male and female islets. Elevation of glucose concentration above 5 mM triggers an electrical activity with a similar glucose dependence in β-cells of both sexes...

KvS proteins are pore-forming voltage-gated potassium channel subunits that must co-assemble into heterotetramers with Kv2.1 ( KCNB1 ) or Kv2.2 ( KCNB2 ) subunits to form functional channels. In mammals, KvS subunits encompass the Kv5.1 ( KCNF1 ), Kv6.1 ( KCNG1 ), Kv6.2 ( KCNG2 ), Kv6.3 ( KCNG3 ), Kv6.4 ( KCNG4 ), Kv8.1 ( KCNV1 ), Kv8.2 ( KCNV2 ), Kv9.1 ( KCNS1 ), Kv9.2 ( KCNS2 ), and Kv9.3 ( KCNS3 ) proteins. While Kv2 proteins are broadly expressed in electrically excitable cells, KvS mRNAs are enriched in unique subsets of these cells...

The distinct organization of Kv2 voltage-gated potassium channels on and near the cell body of brain neurons enables their regulation of action potentials and specialized membrane contact sites. Somatosensory neurons have a pseudounipolar morphology and transmit action potentials from peripheral nerve endings through axons that bifurcate to the spinal cord and the cell body within ganglia including the dorsal root ganglia (DRG). Kv2 channels regulate action potentials in somatosensory neurons, yet little is known about where Kv2 channels are located...

Voltage-gated K + channels of the Kv2 family are highly expressed in brain and play dual roles in regulating neuronal excitability and in organizing endoplasmic reticulum - plasma membrane (ER- PM) junctions. Studies in heterologous cells suggest that the two pore-forming alpha subunits Kv2.1 and Kv2.2 assemble with "electrically silent" KvS subunits to form heterotetrameric channels with distinct biophysical properties. Here, using mass spectrometry-based proteomics, we identified five KvS subunits as components of native Kv2...

AIM: The voltage-gated Kv7.1 channel, in association with the regulatory subunit KCNE1, contributes to the IKs current in the heart. However, both proteins travel to the plasma membrane using different routes. While KCNE1 follows a classical Golgi-mediated anterograde pathway, Kv7.1 is located in endoplasmic reticulum-plasma membrane junctions (ER-PMjs), where it associates with KCNE1 before being delivered to the plasma membrane. METHODS: To characterize the channel routing to these spots we used a wide repertoire of methodologies, such as protein expression analysis (i...

The distinct organization of Kv2 voltage-gated potassium channels on and near the cell body of brain neurons enables their regulation of action potentials and specialized membrane contact sites. Somatosensory neurons have a pseudounipolar morphology and transmit action potentials from peripheral nerve endings through axons that bifurcate to the spinal cord and the cell body within ganglia including the dorsal root ganglia (DRG). Kv2 channels regulate action potentials in somatosensory neurons, yet little is known about where Kv2 channels are located...

Kv2.1 is involved in regulating neuronal excitability and neuronal cell apoptosis, and inhibiting Kv2.1 is a potential strategy to prevent cell death and achieve neuroprotection in ischemic stroke. In this work, a series of novel benzamide derivatives were designed and synthesized as Kv2.1 inhibitors, and extensive structure-activity relationships led to highly potent and selective Kv2.1 inhibitors having IC50 values of 10-8 M. Among them, compound 80 (IC50 = 0.07 μM, selectivity >130 fold over other K+ , Na+ , and Ca2+ ion channels) was able to decrease the apoptosis of HEK293/Kv2...

Glucocorticoids are primary stress hormones that exert neuronal effects via both genomic and non-genomic signaling pathways. However, their rapid non-genomic effects and underlying mechanisms on neural activities remain elusive. In the present study, we investigated the rapid non-genomic effect of glucocorticoids on Kv2.2 channels in cultured HEK293 cells and acute brain slices including cortical pyramidal neurons and calyx-type synapses in the brain stem. We found that cortisol, the endogenous glucocorticoids, rapidly increased Kv2...

Diversity in the functional expression of ion channels contributes to the unique patterns of activity generated in visceral sensory A-type myelinated neurons versus C-type unmyelinated neurons in response to their natural stimuli. In the present study, Kv2 channels were identified as underlying a previously uncharacterized delayed rectifying potassium current expressed in both A- and C- type nodose ganglion neurons. Kv2.1 and 2.2 appear confined to the soma and initial segment of these sensory neurons, however, neither was identified in their central presynaptic terminals projecting onto relay neurons in the nucleus of the solitary tract (nTS)...

Voltage-dependent K+ (Kv) channels are diverse, comprising the classical Shab  - Kv2, Shaker  - Kv1, Shal  - Kv4, and Shaw  - Kv3 families. The Shaker family alone consists of Kv1.1, Kv1.2, Kv1.3, Kv1.4, Kv1.5, Kv1.6, and Kv1.7. Moreover, the Shab family comprises two functional (Kv2.1 and Kv2.2) and several "silent" alpha subunits (Kv2.3, Kv5, Kv6, Kv8, and Kv9), which do not generate K current. However, e.g., Kv8.1, via heteromerization, inhibits outward currents of the same family or even that of Shaw ...

AIMS: Maladaptive ventricular remodeling is a major cause of ventricular arrhythmias following myocardial infarction and adversely impacts the quality of life of affected patients. Vericiguat is a new soluble guanylate cyclase (sGC) activator with cardioprotective properties. However, its effects on myocardial infarction-induced ventricular remodeling and arrhythmias are not fully comprehended; hence, our research evaluated the effect of vericiguat on mice post-myocardial infarction. MATERIALS AND METHODS: Mice were divided into four treatment groups: Sham, Sham+Veri, MI, and MI + Veri...

in silico Kv2.1 is widely expressed in brain, and inhibiting Kv2.1 is a potential strategy to prevent cell death and achieve neuroprotection in ischemic stroke. Herein, an model of Kv2.1 tetramer structure was constructed by employing the AlphaFold-Multimer deep learning method to facilitate the rational discovery of Kv2.1 inhibitors. GaMD was utilized to create an ion transporting trajectory, which was analyzed with HMM to generate multiple representative receptor conformations. The binding site of RY785 and RY796(S) und- er the P-loop was defined with Fpocket program together with the competitive binding electrophysiology assay...

The regulation of membrane potential and the contractility of vascular smooth muscle cells (VSMCs) by voltage-dependent K+ (Kv) potassium channels are well-established. In this study, native VSMCs from rabbit coronary arteries were used to investigate the inhibitory effect of sertindole, an atypical antipsychotic agent, on Kv channels. Sertindole induced dose-dependent inhibition of Kv channels, with an IC50 of 3.13 ± 0.72 μM. Although sertindole did not cause a change in the steady-state activation curve, it did lead to a negative shift in the steady-state inactivation curve...

The Kv2.1 voltage-activated potassium (Kv) channel is a prominent delayed-rectifier Kv channel in the mammalian central nervous system, where its mechanisms of activation and inactivation are critical for regulating intrinsic neuronal excitability1,2 . Here we present structures of the Kv2.1 channel in a lipid environment using cryo-electron microscopy to provide a framework for exploring its functional mechanisms and how mutations causing epileptic encephalopathies3-7 alter channel activity. By studying a series of disease-causing mutations, we identified one that illuminates a hydrophobic coupling nexus near the internal end of the pore that is critical for inactivation...

The voltage-gated proton channel (Hv1) plays an essential role in numerous biological processes, but a detailed molecular understanding of its function is lacking. The lack of reliable structures for the open and resting states is a major handicap. Several models have been built based on homologous voltage sensors and the structure of a chimera between the mouse homologue and a phosphatase voltage sensor, but their validity is uncertain. In addition, differing views exist regarding the mode of proton translocation, the role of specific residues, and the mechanism of pH effects on voltage gating...

Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles in lipid and Ca2+ signaling and homeostasis. Subcellular compartmentalization of protein kinase A (PKA) signaling also regulates essential cellular functions, however, no specific association between PKA and ER-PM junctional domains is known. Here, we show that in brain neurons type I PKA is directed to Kv2...