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Handbook of Experimental Pharmacology 2017This chapter provides a critical overview of the available literature on the pharmacology of mitochondrial potassium channels. In the first part, the reader is... (Review)
Review
This chapter provides a critical overview of the available literature on the pharmacology of mitochondrial potassium channels. In the first part, the reader is introduced to the topic, and eight known protein contributors to the potassium permeability of the inner mitochondrial membrane are presented. The main part of this chapter describes the basic characteristics of each channel type mentioned in the introduction. However, the most important and valuable information included in this chapter concerns the pharmacology of mitochondrial potassium channels. Several available channel modulators are critically evaluated and rated by suitability for research use. The last figure of this chapter shows the results of this evaluation at a glance. Thus, this chapter can be very useful for beginners in this field. It is intended to be a time- and resource-saving guide for those searching for proper modulators of mitochondrial potassium channels.
Topics: Animals; Humans; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Mitochondria; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 27838853
DOI: 10.1007/164_2016_79 -
The Journal of Physiology Jun 2015The most essential properties of ion channels for their physiologically relevant functions are ion-selective permeation and gating. Among the channel species, the... (Review)
Review
The most essential properties of ion channels for their physiologically relevant functions are ion-selective permeation and gating. Among the channel species, the potassium channel is primordial and the most ubiquitous in the biological world, and knowledge of this channel underlies the understanding of features of other ion channels. The strategy applied to studying channels changed dramatically after the crystal structure of the potassium channel was resolved. Given the abundant structural information available, we exploited the bacterial KcsA potassium channel as a simple model channel. In the postcrystal age, there are two effective frameworks with which to decipher the functional codes present in the channel structure, namely reconstitution and re-animation. Complex channel proteins are decomposed into essential functional components, and well-examined parts are rebuilt for integrating channel function in the membrane (reconstitution). Permeation and gating are dynamic operations, and one imagines the active channel by breathing life into the 'frozen' crystal (re-animation). Capturing the motion of channels at the single-molecule level is necessary to characterize the behaviour of functioning channels. Advanced techniques, including diffracted X-ray tracking, lipid bilayer methods and high-speed atomic force microscopy, have been used. Here, I present dynamic pictures of the KcsA potassium channel from the submolecular conformational changes to the supramolecular collective behaviour of channels in the membrane. These results form an integrated picture of the active channel and offer insights into the processes underlying the physiological function of the channel in the cell membrane.
Topics: Cell Membrane; Humans; Ion Channel Gating; Potassium Channels
PubMed: 25833254
DOI: 10.1113/JP270025 -
Expert Opinion on Therapeutic Targets 2023
Topics: Humans; KATP Channels; Potassium Channels; Adenosine Triphosphate
PubMed: 37489110
DOI: 10.1080/14728222.2023.2240023 -
Annual Review of Pharmacology and... Jan 2020The three small-conductance calcium-activated potassium (K2) channels and the related intermediate-conductance K3.1 channel are voltage-independent K channels that... (Review)
Review
The three small-conductance calcium-activated potassium (K2) channels and the related intermediate-conductance K3.1 channel are voltage-independent K channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. K2 and K3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of K channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule K2 and K3.1 modulators. Finally, we describe the progress that has been made in advancing K3.1 blockers and K2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges.
Topics: Animals; Binding Sites; Cardiovascular Diseases; Humans; Intermediate-Conductance Calcium-Activated Potassium Channels; Nervous System Diseases; Potassium Channel Blockers; Small-Conductance Calcium-Activated Potassium Channels
PubMed: 31337271
DOI: 10.1146/annurev-pharmtox-010919-023420 -
Biochimica Et Biophysica Acta.... May 2020Ion channels play crucial roles in cellular biology, physiology, and communication including sensory perception. Voltage-gated potassium (Kv) channels execute their... (Review)
Review
BACKGROUND
Ion channels play crucial roles in cellular biology, physiology, and communication including sensory perception. Voltage-gated potassium (Kv) channels execute their function by sensor activation, pore-coupling, and pore opening leading to K conductance.
SCOPE OF REVIEW
This review focuses on a voltage-gated K ion channel KCNQ1 (Kv 7.1). Firstly, discussing its positioning in the human ion chanome, and the role of KCNQ1 in the multitude of cellular processes. Next, we discuss the overall channel architecture and current structural insights on KCNQ1. Finally, the gating mechanism involving members of the KCNE family and its interaction with non-KCNE partners.
MAJOR CONCLUSIONS
KCNQ1 executes its important physiological functions via interacting with KCNE1 and non-KCNE1 proteins/molecules: calmodulin, PIP, PKA. Although, KCNQ1 has been studied in great detail, several aspects of the channel structure and function still remain unexplored. This review emphasizes the structural and biophysical studies of KCNQ1, its interaction with KCNE1 and non-KCNE1 proteins and focuses on several seminal findings showing the role of VSD and the pore domain in the channel activation and gating properties.
GENERAL SIGNIFICANCE
KCNQ1 mutations can result in channel defects and lead to several diseases including atrial fibrillation and long QT syndrome. Therefore, a thorough structure-function understanding of this channel complex is essential to understand its role in both normal and disease biology. Moreover, unraveling the molecular mechanisms underlying the regulation of this channel complex will help to find therapeutic strategies for several diseases.
Topics: Humans; Ion Channel Gating; Ion Channels; Ion Transport; KCNQ1 Potassium Channel; Long QT Syndrome; Membranes; Potassium; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 31825788
DOI: 10.1016/j.bbamem.2019.183148 -
Genetics Jul 2018Like all species, the model eukaryote , or Bakers' yeast, concentrates potassium in the cytosol as an electrogenic osmolyte and enzyme cofactor. Yeast are capable of... (Review)
Review
Like all species, the model eukaryote , or Bakers' yeast, concentrates potassium in the cytosol as an electrogenic osmolyte and enzyme cofactor. Yeast are capable of robust growth on a wide variety of potassium concentrations, ranging from 10 µM to 2.5 M, due to the presence of a high-affinity potassium uptake system and a battery of cation exchange transporters. Genetic perturbation of either of these systems retards yeast growth on low or high potassium, respectively. However, these potassium-sensitized yeast are a powerful genetic tool, which has been leveraged for diverse studies. Notably, the potassium-sensitive cells can be transformed with plasmids encoding potassium channels from bacteria, plants, or mammals, and subsequent changes in growth rate have been found to correlate with the activity of the introduced potassium channel. Discoveries arising from the use of this assay over the past three decades have increased our understanding of the structure-function relationships of various potassium channels, the mechanisms underlying the regulation of potassium channel function and trafficking, and the chemical basis of potassium channel modulation. In this article, we provide an overview of the major genetic tools used to study potassium channels in , a survey of seminal studies utilizing these tools, and a prospective for the future use of this elegant genetic approach.
Topics: Cytosol; Genetic Engineering; Potassium; Potassium Channels; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 29967058
DOI: 10.1534/genetics.118.301026 -
International Review of Neurobiology 2016Large conductance calcium- and voltage-activated potassium (BK) channels are ubiquitously expressed and play an important role in the regulation of an eclectic array of... (Review)
Review
Large conductance calcium- and voltage-activated potassium (BK) channels are ubiquitously expressed and play an important role in the regulation of an eclectic array of physiological processes. Their diverse functional role requires channels with a wide variety of properties even though the pore-forming α-subunit is encoded by a single gene, KCNMA1. To achieve this, BK channels exploit some of the most fundamental posttranscriptional and posttranslational mechanisms that allow proteomic diversity to be generated from a single gene. These include mechanisms that diversify mRNA variants and abundance such as alternative pre-mRNA splicing, editing, and control by miRNA. The BK channel is also subject to a diverse array of posttranslational modifications including protein phosphorylation, lipidation, glycosylation, and ubiquitination to control the number, properties, and regulation of BK channels in specific cell types. Importantly, "cross talk" between these posttranscriptional and posttranslational modifications typically converge on disordered domains of the BK channel α-subunit. This allows both wide physiological diversity to be generated and a diversity of mechanisms to allow conditional regulation of BK channels and is emerging as an important determinant of BK channel function in health and disease.
Topics: Animals; Humans; Ion Channel Gating; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Large-Conductance Calcium-Activated Potassium Channels; Models, Molecular; Protein Processing, Post-Translational; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 27238262
DOI: 10.1016/bs.irn.2016.02.012 -
Biological Chemistry Sep 2019Potassium channels play a crucial role in the physiology of all living organisms. They maintain the membrane potential and are involved in electrical signaling, pH... (Review)
Review
Potassium channels play a crucial role in the physiology of all living organisms. They maintain the membrane potential and are involved in electrical signaling, pH homeostasis, cell-cell communication and survival under osmotic stress. Many prokaryotic potassium channels and members of the eukaryotic Slo channels are regulated by tethered cytoplasmic domains or associated soluble proteins, which belong to the family of regulator of potassium conductance (RCK). RCK domains and subunits form octameric rings, which control ion gating. For years, a common regulatory mechanism was suggested: ligand-induced conformational changes in the octameric ring would pull open a gate in the pore via flexible linkers. Consistently, ligand-dependent conformational changes were described for various RCK gating rings. Yet, recent structural and functional data of complete ion channels uncovered that the following signal transduction to the pore domains is divers. The different RCK-regulated ion channels show remarkably heterogeneous mechanisms with neither the connection from the RCK domain to the pore nor the gate being conserved. Some channels even lack the flexible linkers, while in others the gate cannot easily be assigned. In this review we compare available structures of RCK-gated potassium channels, highlight the similarities and differences of channel gating, and delineate existing inconsistencies.
Topics: Adenosine Diphosphate; Bacterial Proteins; Calcium; Hydrogen-Ion Concentration; Ion Channel Gating; Potassium Channels; Protein Conformation; Protein Domains; Sodium
PubMed: 31361596
DOI: 10.1515/hsz-2019-0153 -
Cell Reports Aug 2023The sodium-activated Slo2.2 channel is abundantly expressed in the brain, playing a critical role in regulating neuronal excitability. The Na-binding site and the...
The sodium-activated Slo2.2 channel is abundantly expressed in the brain, playing a critical role in regulating neuronal excitability. The Na-binding site and the underlying mechanisms of Na-dependent activation remain unclear. Here, we present cryoelectron microscopy (cryo-EM) structures of human Slo2.2 in closed, open, and inhibitor-bound form at resolutions of 2.6-3.2 Å, revealing gating mechanisms of Slo2.2 regulation by cations and a potent inhibitor. The cytoplasmic gating ring domain of the closed Slo2.2 harbors multiple K and Zn sites, which stabilize the channel in the closed conformation. The open Slo2.2 structure reveals at least two Na-sensitive sites where Na binding induces expansion and rotation of the gating ring that opens the inner gate. Furthermore, a potent inhibitor wedges into a pocket formed by pore helix and S6 helix and blocks the pore. Together, our results provide a comprehensive structural framework for the investigation of Slo2.2 channel gating, Na sensation, and inhibition.
Topics: Humans; Potassium Channels; Cryoelectron Microscopy; Potassium Channels, Sodium-Activated; Sodium
PubMed: 37494189
DOI: 10.1016/j.celrep.2023.112858 -
International Journal of Molecular... Feb 2019Ion channels are transmembrane proteins that conduct specific ions across biological membranes. Ion channels are present at the onset of many cellular processes, and... (Review)
Review
Ion channels are transmembrane proteins that conduct specific ions across biological membranes. Ion channels are present at the onset of many cellular processes, and their malfunction triggers severe pathologies. Potassium channels (KChs) share a highly conserved signature that is necessary to conduct K⁺ through the pore region. To be functional, KChs require an exquisite regulation of their subcellular location and abundance. A wide repertoire of signatures facilitates the proper targeting of the channel, fine-tuning the balance that determines traffic and location. These signature motifs can be part of the secondary or tertiary structure of the protein and are spread throughout the entire sequence. Furthermore, the association of the pore-forming subunits with different ancillary proteins forms functional complexes. These partners can modulate traffic and activity by adding their own signatures as well as by exposing or masking the existing ones. Post-translational modifications (PTMs) add a further dimension to traffic regulation. Therefore, the fate of a KCh is not fully dependent on a gene sequence but on the balance of many other factors regulating traffic. In this review, we assemble recent evidence contributing to our understanding of the spatial expression of KChs in mammalian cells. We compile specific signatures, PTMs, and associations that govern the destination of a functional channel.
Topics: Animals; Biological Transport; Cell Membrane; Humans; Intracellular Space; Ion Channel Gating; Organelles; Potassium; Potassium Channels; Protein Binding; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Processing, Post-Translational; Signal Transduction
PubMed: 30744118
DOI: 10.3390/ijms20030734