Competitive modulation of K1.2 gating by LMAN2 and Slc7a5.

K1.2 is a prominent ion channel in the CNS, where it regulates neuronal excitability. K1.

Regulation of Kv1.2 Redox-Sensitive Gating by the Transmembrane Lectin LMAN2.

Voltage gated potassium (Kv)1.2 channels influence excitability and action potential propagation in the nervous system. Unlike closely related Kv1 channels, Kv1.

Unmasking subtype-dependent susceptibility to C-type inactivation in mammalian Kv1 channels.

Shaker potassium channels have been an essential model for studying inactivation of ion channels and shaped our earliest understanding of N-type vs. C-type mechanisms. In early work describing C-type inactivation, López-Barneo and colleagues systematically characterized numerous mutations of Shaker residue T449, demonstrating that this position was a key determinant of C-type inactivation rate.

Reducing agents facilitate membrane patch seal integrity and longevity.

The patch clamp method is a widely applied electrophysiological technique used to understand ion channel activity and cellular excitation. The formation of a high resistance giga-ohm seal is required to obtain high-quality recordings but can be challenging due to variables including operator experience and cell preparation. Therefore, the identification of methods to promote the formation and longevity of giga-ohm seals may be beneficial.

Site and Mechanism of ML252 Inhibition of Kv7 Voltage-Gated Potassium Channels.

Kv7 (KCNQ) voltage-gated potassium channels are critical regulators of neuronal excitability and are candidate targets for development of antiseizure medications. Drug discovery efforts have identified small molecules that modulate channel function and reveal mechanistic insights into Kv7 channel physiological roles. While Kv7 channel activators have therapeutic benefits, inhibitors are useful for understanding channel function and mechanistic validation of candidate drugs.

Familial neonatal seizures caused by the Kv7.3 selectivity filter mutation T313I.

Objective: A spectrum of seizure disorders is linked to mutations in Kv7.2 and Kv7.3 channels.

Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels.

Many voltage-dependent ion channels are regulated by accessory proteins. We recently reported powerful regulation of Kv1.2 potassium channels by the amino acid transporter Slc7a5.

A structure-based computational workflow to predict liability and binding modes of small molecules to hERG.

Off-target interactions of drugs with the human ether-à-go-go related gene 1 (hERG1) channel have been associated with severe cardiotoxic conditions leading to the withdrawal of many drugs from the market over the last decades. Consequently, predicting drug-induced hERG-liability is now a prerequisite in any drug discovery campaign. Understanding the atomic level interactions of drug with the channel is essential to guide the efficient development of safe drugs.

Endoplasmic reticulum stress in the dorsal root ganglia regulates large-conductance potassium channels and contributes to pain in a model of multiple sclerosis.

Neuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post-mortem DRGs from MS patients.

Heteromeric Assembly of Truncated Neuronal Kv7 Channels: Implications for Neurologic Disease and Pharmacotherapy.

Neuronal voltage-gated potassium channels (Kv) are critical regulators of electrical activity in the central nervous system. Mutations in the KCNQ (Kv7) ion channel family are linked to epilepsy and neurodevelopmental disorders. These channels underlie the neuronal "M-current" and cluster in the axon initial segment to regulate the firing of action potentials.

Slc7a5 alters Kvβ-mediated regulation of Kv1.2.

The voltage-gated potassium channel Kv1.2 plays a pivotal role in neuronal excitability and is regulated by a variety of known and unknown extrinsic factors. The canonical accessory subunit of Kv1.

Differential Regulation of Human Ether-à-Go-Go-Related Gene (hERG) Current and Expression by Activation of Protein Kinase C.

The () encodes the channel that conducts the rapidly activating delayed rectifier potassium current (I) in the heart. Reduction in I causes long QT syndrome, which can lead to fatal arrhythmias triggered by stress. One potential link between stress and hERG function is protein kinase C (PKC) activation; however, seemingly conflicting results regarding PKC regulation of hERG have been reported.

Anti-Ro52 antibody acts on the S5-pore linker of hERG to chronically reduce channel expression.

Aims: The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (IKr). Malfunction of hERG/IKr is the primary cause of acquired long QT syndrome (LQTS), an electrical disorder of the heart that can cause arrhythmias and sudden death. Patients with autoimmune diseases display a high incidence of LQTS.

Pore- and voltage sensor-targeted KCNQ openers have distinct state-dependent actions.

Ion channels encoded by generate a prominent K conductance in the central nervous system, referred to as the M current, which is controlled by membrane voltage and PIP2. The KCNQ2-5 voltage-gated potassium channels are targeted by a variety of activating compounds that cause negative shifts in the voltage dependence of activation. The underlying pharmacology of these effects is of growing interest because of possible clinical applications.

The N terminus and transmembrane segment S1 of Kv1.5 can coassemble with the rest of the channel independently of the S1-S2 linkage.

The voltage-gated potassium channel Kv1.5 belongs to the Shaker superfamily. Kv1.

Glycosylation stabilizes hERG channels on the plasma membrane by decreasing proteolytic susceptibility.

The human ether-a-go-go related gene (hERG)-encoded channel hERG undergoes N-linked glycosylation at position 598, which is located in the unusually long S5-pore linker of the channel. In other work we have demonstrated that hERG is uniquely susceptible to proteolytic cleavage at the S5-pore linker by proteinase K (PK) and calpain (CAPN). The scorpion toxin BeKm-1, which binds to the S5-pore linker of hERG, protects hERG from such cleavage.

Hypoxia reduces mature hERG channels through calpain up-regulation.

Human -related gene () encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current () potassium channel, which is important for cardiac repolarization. Impairment of hERG function is the primary cause of acquired long QT syndrome, which predisposes individuals to cardiac arrhythmias and sudden death. Patients with hypoxia due to conditions such as cardiac ischemia or obstructive sleep apnea display increased incidence of cardiac arrhythmias and sudden death.

-Arrestin-Mediated Regulation of the Human -Related Gene Potassium Channel.

The rapidly activating delayed rectifier K channel (I) is encoded by the human -related gene (), which is important for the repolarization of the cardiac action potential. Mutations in hERG or drugs can impair the function or decrease the expression level of hERG channels, leading to long QT syndrome. Thus, it is important to understand hERG channel trafficking and its regulation.

The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage.

The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome and sudden death, which occur in patients with cardiac ischemia. Cardiac ischemia is also associated with activation, up-regulation, and secretion of various proteolytic enzymes.

Febrile temperature facilitates hERG/IKr degradation through an altered K(+) dependence.

Background: Dysfunction of the rapidly activating delayed rectifier K(+) channel (IKr) encoded by the human ether-à-go-go-related gene (hERG) is the primary cause of acquired long QT syndrome (LQTS). Fever has been reported to trigger LQTS in various conditions.

Objective: We aim to clarify the effect and underlying mechanisms of febrile temperature on hERG expressed in HEK cells, IKr in neonatal rat ventricular myocytes, and the QT interval in rabbits.

Rab11-dependent Recycling of the Human Ether-a-go-go-related Gene (hERG) Channel.

The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr). A reduction in the hERG current causes long QT syndrome, which predisposes affected individuals to ventricular arrhythmias and sudden death. We reported previously that hERG channels in the plasma membrane undergo vigorous internalization under low K(+) conditions.

Muscarinic receptor activation increases hERG channel expression through phosphorylation of ubiquitin ligase Nedd4-2.

The human ether-à-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel, which is important for cardiac repolarization. Reduction of hERG current due to genetic mutations or drug interferences causes long QT syndrome, leading to cardiac arrhythmias and sudden death. To date, there is no effective therapeutic method to restore or enhance hERG channel function.

The serum- and glucocorticoid-inducible kinases SGK1 and SGK3 regulate hERG channel expression via ubiquitin ligase Nedd4-2 and GTPase Rab11.

The hERG (human ether-a-go-go-related gene) encodes the α subunit of the rapidly activating delayed rectifier potassium channel (IKr). Dysfunction of hERG channels due to mutations or certain medications causes long QT syndrome, which can lead to fatal ventricular arrhythmias or sudden death. Although the abundance of hERG in the plasma membrane is a key determinant of hERG functionality, the mechanisms underlying its regulation are not well understood.