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Nature Communications Apr 2024The analysis of neural circuits has been revolutionized by optogenetic methods. Light-gated chloride-conducting anion channelrhodopsins (ACRs)-recently emerged as...
The analysis of neural circuits has been revolutionized by optogenetic methods. Light-gated chloride-conducting anion channelrhodopsins (ACRs)-recently emerged as powerful neuron inhibitors. For cells or sub-neuronal compartments with high intracellular chloride concentrations, however, a chloride conductance can have instead an activating effect. The recently discovered light-gated, potassium-conducting, kalium channelrhodopsins (KCRs) might serve as an alternative in these situations, with potentially broad application. As yet, KCRs have not been shown to confer potent inhibitory effects in small genetically tractable animals. Here, we evaluated the utility of KCRs to suppress behavior and inhibit neural activity in Drosophila, Caenorhabditis elegans, and zebrafish. In direct comparisons with ACR1, a KCR1 variant with enhanced plasma-membrane trafficking displayed comparable potency, but with improved properties that include reduced toxicity and superior efficacy in putative high-chloride cells. This comparative analysis of behavioral inhibition between chloride- and potassium-selective silencing tools establishes KCRs as next-generation optogenetic inhibitors for in vivo circuit analysis in behaving animals.
Topics: Animals; Caenorhabditis elegans; Neurons; Optogenetics; Zebrafish; Channelrhodopsins; Humans; Drosophila; Potassium Channels; Chlorides; Animals, Genetically Modified; Behavior, Animal; HEK293 Cells; Drosophila melanogaster
PubMed: 38658537
DOI: 10.1038/s41467-024-47203-w -
Life Science Alliance Dec 2023Voltage-sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in...
Voltage-sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large-scale analysis of 897 patients with gastro-oesophageal adenocarcinomas (GOAs) coupled with in vitro models, we find family genes are mutated in ∼30% of patients, and play therapeutically targetable roles in GOA cancer growth. and mediate the WNT pathway and MYC to increase proliferation through resultant effects on cadherin junctions. This also highlights novel roles of in non-excitable tissues. We also discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors and that inhibition of KCNQ activity reduces proliferation of GOA cancer cells. These findings reveal a novel and exploitable role of potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GOAs may exist through KCNQ inhibitors.
Topics: Humans; KCNQ Potassium Channels; KCNQ3 Potassium Channel; KCNQ2 Potassium Channel; Adenocarcinoma
PubMed: 37748809
DOI: 10.26508/lsa.202302124 -
International Journal of Molecular... Jul 2023Sperm cells must undergo a complex maturation process after ejaculation to be able to fertilize an egg. One component of this maturation is hyperpolarization of the... (Review)
Review
Sperm cells must undergo a complex maturation process after ejaculation to be able to fertilize an egg. One component of this maturation is hyperpolarization of the membrane potential to a more negative value. The ion channel responsible for this hyperpolarization, SLO3, was first cloned in 1998, and since then much progress has been made to determine how the channel is regulated and how its function intertwines with various signaling pathways involved in sperm maturation. Although was originally thought to be present only in the sperm of mammals, recent evidence suggests that a primordial form of the gene is more widely expressed in some fish species. , like many reproductive genes, is rapidly evolving with low conservation between closely related species and different regulatory and pharmacological profiles. Despite these differences, SLO3 appears to have a conserved role in regulating sperm membrane potential and driving large changes in response to stimuli. The effect of this hyperpolarization of the membrane potential may vary among mammalian species just as the regulation of the channel does. Recent discoveries have elucidated the role of SLO3 in these processes in human sperm and provided tools to target the channel to affect human fertility.
Topics: Animals; Male; Humans; Membrane Potentials; Large-Conductance Calcium-Activated Potassium Channels; Semen; Spermatozoa; Signal Transduction; Mammals
PubMed: 37446382
DOI: 10.3390/ijms241311205 -
Neuroscience and Biobehavioral Reviews Sep 2023Potassium channels (K-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability.... (Review)
Review
Potassium channels (K-channels) selectively control the passive flow of potassium ions across biological membranes and thereby also regulate membrane excitability. Genetic variants affecting many of the human K-channels are well known causes of Mendelian disorders within cardiology, neurology, and endocrinology. K-channels are also primary targets of many natural toxins from poisonous organisms and drugs used within cardiology and metabolism. As genetic tools are improving and larger clinical samples are being investigated, the spectrum of clinical phenotypes implicated in K-channels dysfunction is rapidly expanding, notably within immunology, neurosciences, and metabolism. K-channels that previously were considered to be expressed in only a few organs and to have discrete physiological functions, have recently been found in multiple tissues and with new, unexpected functions. The pleiotropic functions and patterns of expression of K-channels may provide additional therapeutic opportunities, along with new emerging challenges from off-target effects. Here we review the functions and therapeutic potential of K-channels, with an emphasis on the nervous system, roles in neuropsychiatric disorders and their involvement in other organ systems and diseases.
Topics: Humans; Potassium Channels; Brain Diseases; Potassium
PubMed: 37414376
DOI: 10.1016/j.neubiorev.2023.105301 -
Biomolecules Dec 2023The malignancy of glioblastoma (GBM), the most aggressive type of human brain tumor, strongly correlates with the presence of hypoxic areas within the tumor mass. Oxygen... (Review)
Review
The malignancy of glioblastoma (GBM), the most aggressive type of human brain tumor, strongly correlates with the presence of hypoxic areas within the tumor mass. Oxygen levels have been shown to control several critical aspects of tumor aggressiveness, such as migration/invasion and cell death resistance, but the underlying mechanisms are still unclear. GBM cells express abundant K and Cl channels, whose activity supports cell volume and membrane potential changes, critical for cell proliferation, migration and death. Volume-regulated anion channels (VRAC), which mediate the swelling-activated Cl current, and the large-conductance Ca-activated K channels (BK) are both functionally upregulated in GBM cells, where they control different aspects underlying GBM malignancy/aggressiveness. The functional expression/activity of both VRAC and BK channels are under the control of the oxygen levels, and these regulations are involved in the hypoxia-induced GBM cell aggressiveness. The present review will provide a comprehensive overview of the literature supporting the role of these two channels in the hypoxia-mediated GBM malignancy, suggesting them as potential therapeutic targets in the treatment of GBM.
Topics: Humans; Glioblastoma; Large-Conductance Calcium-Activated Potassium Channels; Cell Line, Tumor; Hypoxia; Oxygen
PubMed: 38136613
DOI: 10.3390/biom13121742 -
Channels (Austin, Tex.) Dec 2023Sex hormones and the reproductive cycle (estrus in rodents and menstrual in humans) have a known impact on arterial function. In spite of this, sex hormones and the... (Review)
Review
Sex hormones and the reproductive cycle (estrus in rodents and menstrual in humans) have a known impact on arterial function. In spite of this, sex hormones and the estrus/menstrual cycle are often neglected experimental factors in vascular basic preclinical scientific research. Recent research by our own laboratory indicates that cyclical changes in serum concentrations of sex -hormones across the rat estrus cycle, primary estradiol, have significant consequences for the subcellular trafficking and function of K. Vascular potassium channels, including K, are essential components of vascular reactivity. Our study represents a small part of a growing field of literature aimed at determining the role of sex hormones in regulating arterial ion channel function. This review covers key findings describing the current understanding of sex hormone regulation of vascular potassium channels, with a focus on K channels. Further, we highlight areas of research where the estrus cycle should be considered in future studies to determine the consequences of physiological oscillations in concentrations of sex hormones on vascular potassium channel function.
Topics: Female; Humans; Rats; Animals; Progesterone; Potassium Channels; Gonadal Steroid Hormones; Estradiol; Menstrual Cycle
PubMed: 37243715
DOI: 10.1080/19336950.2023.2217637 -
Nature Communications Jul 2023Inwardly rectifying potassium (Kir) channels open at the 'helix bundle crossing' (HBC), formed by the M2 helices at the cytoplasmic end of the transmembrane pore....
Inwardly rectifying potassium (Kir) channels open at the 'helix bundle crossing' (HBC), formed by the M2 helices at the cytoplasmic end of the transmembrane pore. Introduced negative charges at the HBC (G178D) in Kir2.2 channels forces opening, allowing pore wetting and free movement of permeant ions between the cytoplasm and the inner cavity. Single-channel recordings reveal striking, pH-dependent, subconductance behaviors in G178D (or G178E and equivalent Kir2.1[G177E]) mutant channels, with well-resolved non-cooperative subconductance levels. Decreasing cytoplasmic pH shifts the probability towards lower conductance levels. Molecular dynamics simulations show how protonation of Kir2.2[G178D], or the D173 pore-lining residues, changes solvation, K ion occupancy, and K conductance. Ion channel gating and conductance are classically understood as separate processes. The present data reveal how individual protonation events change the electrostatic microenvironment of the pore, resulting in step-wise alterations of ion pooling, and hence conductance, that appear as 'gated' substates.
Topics: Ions; Molecular Dynamics Simulation; Cytoplasm; Oocytes
PubMed: 37507406
DOI: 10.1038/s41467-023-40058-7 -
International Journal of Molecular... May 2024Oocyte-cumulus cell interaction is essential for oocyte maturation and competence. The bidirectional crosstalk network mediated by gap junctions is fundamental for the... (Review)
Review
Oocyte-cumulus cell interaction is essential for oocyte maturation and competence. The bidirectional crosstalk network mediated by gap junctions is fundamental for the metabolic cooperation between these cells. As cumulus cells exhibit a more glycolytic phenotype, they can provide metabolic substrates that the oocyte can use to produce ATP via oxidative phosphorylation. The impairment of mitochondrial activity plays a crucial role in ovarian aging and, thus, in fertility, determining the success or failure of assisted reproductive techniques. This review aims to deepen the knowledge about the electro-metabolic coupling of the cumulus-oocyte complex and to hypothesize a putative role of potassium channel modulators in order to improve fertility, promote intracellular Ca influx, and increase the mitochondrial biogenesis and resulting ATP levels in cumulus cells.
Topics: Oocytes; Cumulus Cells; Humans; Animals; Female; Mitochondria; Adenosine Triphosphate; Gap Junctions; Oxidative Phosphorylation; Calcium; Potassium Channels; Cell Communication
PubMed: 38791387
DOI: 10.3390/ijms25105349 -
Nature Chemical Biology Jan 2024Quaternary ammonium blockers were previously shown to bind in the pore to block both open and closed conformations of large-conductance calcium-activated potassium (BK...
Quaternary ammonium blockers were previously shown to bind in the pore to block both open and closed conformations of large-conductance calcium-activated potassium (BK and MthK) channels. Because blocker entry was assumed through the intracellular entryway (bundle crossing), closed-pore access suggested that the gate was not at the bundle crossing. Structures of closed MthK, a Methanobacterium thermoautotrophicum homolog of BK channels, revealed a tightly constricted intracellular gate, leading us to investigate the membrane-facing fenestrations as alternative pathways for blocker access directly from the membrane. Atomistic free energy simulations showed that intracellular blockers indeed access the pore through the fenestrations, and a mutant channel with narrower fenestrations displayed no closed-state TPeA block at concentrations that blocked the wild-type channel. Apo BK channels display similar fenestrations, suggesting that blockers may use them as access paths into closed channels. Thus, membrane fenestrations represent a non-canonical pathway for selective targeting of specific channel conformations, opening novel ways to selectively drug BK channels.
Topics: Large-Conductance Calcium-Activated Potassium Channels; Calcium; Calcium Channels; Potassium; Molecular Conformation
PubMed: 37653172
DOI: 10.1038/s41589-023-01406-2 -
International Journal of Molecular... Jun 2023Abnormalities in G-protein-gated inwardly rectifying potassium (GIRK) channels have been implicated in diseased states of the cardiovascular system; however, the role of... (Review)
Review
Abnormalities in G-protein-gated inwardly rectifying potassium (GIRK) channels have been implicated in diseased states of the cardiovascular system; however, the role of GIRK4 (Kir3.4) in cardiac physiology and pathophysiology has yet to be completely understood. Within the heart, the K channel, consisting of two GIRK1 and two GIRK4 subunits, plays a major role in modulating the parasympathetic nervous system's influence on cardiac physiology. Being that GIRK4 is necessary for the functional K channel, , which encodes GIRK4, it presents as a therapeutic target for cardiovascular pathology. Human variants in have been identified in familial hyperaldosteronism type III, long QT syndrome, atrial fibrillation, and sinus node dysfunction. Here, we explore the relevance of in each of these diseases. Further, we address the limitations and complexities of discerning the role of in cardiovascular pathophysiology, as identical human variants of have been identified in several diseases with overlapping pathophysiology.
Topics: Humans; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Heart; Sick Sinus Syndrome; Hyperaldosteronism; Long QT Syndrome
PubMed: 37446026
DOI: 10.3390/ijms241310849