Maxik

INTRODUCTION: Opinions differ on what drugs have both a rationale and a development potential for the treatment of bladder storage dysfunction. AREAS COVERED: In the present review, the focus is given to small molecule blockers of TRP channels (TRPV1, TRPV4, TRPA1, and TRPM8), P2×3receptor antagonists, drugs against oxidative stress, antifibrosis agents, cyclic nucleotide - dependent pathways, and MaxiK±channel - gene therapy. EXPERT OPINION: TRPV1 channel blockers produce hypothermia which seems to be a problem even with the most efficacious second-generation TRPV1 antagonists...

Mammalian Ca2+ -dependent Slo K+ channels can stably associate with auxiliary γ subunits which fundamentally alter their behavior. By a so far unknown mechanism, the four γ subunits reduce the need for voltage-dependent activation and, thereby, allow Slo to open independently of an action potential. Here, using cryo-EM, we reveal how the transmembrane helix of γ1/LRRC26 binds and presumably stabilizes the activated voltage-sensor domain of Slo1. The activation is further enhanced by an intracellular polybasic stretch which locally changes the charge gradient across the membrane...

Despite the significant number of people who may be taking pregnenolone supplements while drinking alcohol (ethanol), the widely documented cerebrovascular actions of pregnenolone and ethanol, and the critical dependence of cerebrovascular function on cerebral artery diameter, there are no studies addressing the effect of pregnenolone + ethanol in combination on cerebral artery diameter. We investigated this by evaluating the effect of this combination on middle cerebral artery diameter in male and female C57BL/6J mice, both in vivo and in vitro ...

The large-conductance Ca2+ -activated K+ (BK) channel is widely expressed in the pulmonary blood vessels and plays a significant role in regulating pulmonary vascular tonus. It opens under membrane depolarization, increased intracellular Ca+2 concentration, and chronic hypoxia, resulting in massive K+ efflux, membrane hyperpolarization, decreased L-type Ca+2 channel opening, and smooth muscle relaxation. Several reports have demonstrated an association between BK channel dysfunction and pulmonary hypertension (PH) development...

Calcium/voltage-activated potassium channels (BK) control smooth muscle (SM) tone and cerebral artery diameter. They include channel-forming α and regulatory β1 subunits, the latter being highly expressed in SM. Both subunits participate in steroid-induced modification of BK activity: β1 provides recognition for estradiol and cholanes, resulting in BK potentiation, whereas α suffices for BK inhibition by cholesterol or pregnenolone. Aldosterone can modify cerebral artery function independently of its effects outside the brain, yet BK involvement in aldosterone's cerebrovascular action and identification of channel subunits, possibly involved in steroid action, remains uninvestigated...

BK K+ channels are critical regulators of neuron and muscle excitability, comprised of a tetramer of pore-forming αsubunits from the KCNMA1 gene and cell- and tissue-selective β subunits ( KCNMB1-4 ). Mutations in KCNMA1 are associated with neurological disorders, including autism. However, little is known about the role of neuronal BK channel β subunits in human neuropathology. The β2 subunit is expressed in central neurons and imparts inactivation to BK channels, as well as altering activation and deactivation gating...

Large conductance, calcium/voltage-gated potassium channels (BK) regulate critical body processes, including neuronal, secretory and smooth muscle (SM) function. While BK-forming alpha subunits are ubiquitous, accessory beta1 subunits are highly expressed in SM. This makes beta1 an attractive target for pharmaceutical development to treat SM disorders, such as hypertension or cerebrovascular spasm. Compounds activating BK via beta1 have been identified, yet they exhibit low potency and off-target effects while antagonists that limit agonist activity via beta 1 remain unexplored...

Abundant findings including our previous work proved that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome exerts a key role in the process of neuroinflammation following blast-induced traumatic brain injury (bTBI). The opening of potassium channels leads to low K+ environment in cells, which appears to be an essential requirement for NLRP3 inflammasome activation. Notably, MaxiK (BK) channel is significant for K+ transport. The present study is aim to investigate the potential role of MaxiK in the activation of NLRP3 and to evaluate whether MaxiK channel blocker paxilline could confer beneficial effects on attenuating the severity of bTBI in rats...

KCNMA1 -linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. KCNMA1 encodes the BK K+ channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations...

Calcium-/voltage-gated, large-conductance potassium channels (BKs) control critical physiological processes, including smooth muscle contraction. Numerous observations concur that elevated membrane cholesterol (CLR) inhibits the activity of homomeric BKs consisting of channel-forming alpha subunits. In mammalian smooth muscle, however, native BKs include accessory KCNMB1 (β1 ) subunits which enable BK activation at physiological intracellular calcium. Here, we studied the effect of CLR-enrichment on BK currents from rat cerebral artery myocytes...

Arachidonic acid (AA) is a fatty acid involved in the modulation of several ion channels. Previously, we reported that AA activates the high conductance Ca2+ - and voltage-dependent K+ channel (BK) in vascular smooth muscle depending on the expression of the auxiliary β1 subunit. Here, using the patch-clamp technique on BK channel co-expressed with β1 subunit in a heterologous cell expression system, we analyzed whether AA modifies the three functional modules involved in the channel gating: the voltage sensor domain (VSD), the pore domain (PD), and the intracellular calcium sensor domain (CSD)...

Alcohol constricts cerebral arteries via inhibition of voltage/calcium-gated, large conductance potassium (BK) channels in vascular myocytes. Using a rat model of high-cholesterol (high-CLR) diet and CLR enrichment of cerebral arteries in vitro, we recently showed that CLR protected against alcohol-induced constriction of cerebral arteries. The subcellular mechanism(s) underlying CLR protection against alcohol-induced constriction of the artery is unclear. Here we use a rat model of high-CLR diet and patch-clamp recording of BK channels in inside-out patches from cerebral artery myocytes to demonstrate that this diet antagonizes inhibition of BK currents by 50 mM ethanol...

A significant portion of the U.S. population may experience vaccine hesitancy of a new COVID-19 vaccine, which poses dangers to both the individual and their community, since exposure to a contagious disease places the person at risk, and individuals are far more likely to spread the disease to others if they do not get vaccinated. Many individuals are doubtful, and without the healthcare community, speaking with one voice has led to distrust. Experience from the influenza vaccines have shown vaccine acceptance has not been optimal, and this new vaccine, even though it is not approved, is already showing layperson skepticism compounded by political influences...

The present study assessed the effect of nearby construction activity on the responses of rat middle cerebral arteries (MCA)to the endothelium-dependent vasodilator acetylcholine and the NO donor sodium nitroprusside (SNP) and the activity of MaxiK potassium channels in MCA smooth muscle cells from male Sprague-Dawley rats. Two monitoring systems were used to assess vibrations in the animal rooms during and immediately after construction activities near the research building where the animal facility is located...

Sublethal exposure to neonicotinoids affects honey bee olfaction, but few studies have investigated the sublethal effects of the enantioselective neonicotinoid dinotefuran on honey bee olfaction. This study assessed the sublethal olfactory toxicity of dinotefuran enantiomers to honey bees. Compared to R-dinotefuran, S-dinotefuran had higher acute oral toxicity, sucrose sensitivity effects and octopamine concentrations and lower learning ability and memory effects on honey bees. High-throughput circular RNA sequencing of the honey bee brain revealed that R-dinotefuran caused more gene regulatory changes than S-dinotefuran...

The differentiation of fibroblasts to myofibroblasts is critical to the development of fibrotic disorders, including idiopathic pulmonary fibrosis (IPF). Previously, we demonstrated that fibroblasts from patients with IPF exhibit changes in DNA methylation across the genome that contribute to a pro-fibrotic phenotype. One of the top differentially methylated genes identified in our previous study was KCNMB1 , which codes for the beta subunit of the large conductance potassium channel (BK, MaxiK, KCa1.1). Here, we examine how the expression of KCNMB1 differs in IPF fibroblasts compared to normal cells, and how BK channels affect myofibroblast differentiation...

BACKGROUND: Fibroblast-like synoviocytes (FLS) and CCR7- effector memory T (TEM ) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA). In particular, FLS become highly invasive, whereas TEM cells proliferate and secrete proinflammatory cytokines, during RA. FLS and T cells may also interact and influence each other's phenotypes. Inhibition of the pathogenic phenotypes of both FLS and TEM cells can be accomplished by selectively blocking the predominant potassium channels that they upregulate during RA: KCa1...

The big conductance Ca2+ dependent K+ channel also known as BK, MaxiK, Slo1 or KCa1.1 is a ligand- and voltage gated K+ channel. Although, structure-function studies of the past decades, involving mutagenesis and electrophysiological measurements revealed fine details of the mechanism of BK channel gating, the exact molecular details remained unknown until the quaternary structure of the protein has been solved at a resolution of 3.5 Å using cryo-electron microscopy. In this short review, we are going to summarize these results and interpret the gating model of the BK channel in the light of the recent structural results...

CONTEXT: Dihydromyricetin (DMY) has oxidation resistance, anti-inflammatory and free radical scavenging capabilities. The preventive effects of DMY for vascular hyporeactivity remain unclear. OBJECTIVE: This study investigates the preventive effects of DMY in vascular hyporeactivity. MATERIALS AND METHODS: The experimental sepsis was induced by transvenous administration of lipopolysaccharide (LPS) to Sprague-Dawley (SD) rats. DMY-treated rats received daily administration of DMY, 5 μg/kg dissolved in DMSO through the tail vein for 7 days...

There is increasing evidence for a role of MaxiK potassium channel-activity in regulating the metabolism and intracellular signaling of non-contractile bladder mucosal tissues. At present however no studies have determined the impact of urothelial MaxiK-activity on overall bladder metabolism. To address this we have investigated the effect of bladder lumen instillation of the MaxiK inhibitor, iberiotoxin (IBTX), on mucosal and detrusor metabolism using metabolomics. Since IBTX does not cross plasma membranes, when instilled into the bladder lumen it would only effect urothelially expressed MaxiK-activity...