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Biophysical Journal Jun 2022Hyperpolarization-activated cyclic-nucleotide gated channels (HCNs) are responsible for the generation of pacemaker currents (I or I) in cardiac and neuronal cells....
Hyperpolarization-activated cyclic-nucleotide gated channels (HCNs) are responsible for the generation of pacemaker currents (I or I) in cardiac and neuronal cells. Despite the overall structural similarity to voltage-gated potassium (Kv) channels, HCNs show much lower selectivity for K over Na ions. This increased permeability to Na is critical to their role in membrane depolarization. HCNs can also select between Na and Li ions. Here, we investigate the unique ion selectivity properties of HCNs using molecular-dynamics simulations. Our simulations suggest that the HCN1 pore is flexible and dilated compared with Kv channels with only one stable ion binding site within the selectivity filter. We also observe that ion coordination and hydration differ within the HCN1 selectivity filter compared with those in Kv and cyclic-nucleotide gated channels. Additionally, the C358T mutation further stabilizes the symmetry of the binding site and provides a more fit space for ion coordination, particularly for Li.
Topics: Cyclic Nucleotide-Gated Cation Channels; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ions; Nucleotides; Potassium; Potassium Channels; Sodium
PubMed: 35474263
DOI: 10.1016/j.bpj.2022.04.024 -
Journal of Chemical Theory and... May 2023Potassium channels are responsible for the selective yet efficient permeation of potassium ions across cell membranes. Despite many available high-resolution structures...
Potassium channels are responsible for the selective yet efficient permeation of potassium ions across cell membranes. Despite many available high-resolution structures of potassium channels, those conformations inform only on static information on the ion permeation processes. Here, we use molecular dynamics simulations and Markov state models to obtain dynamical details of ion permeation. The permeation cycles, expressed in terms of selectivity filter occupancy and representing ion permeation events, are illustrated. We show that the direct knock-on permeation represents the dominant permeation mechanism over a wide range of potassium concentrations, temperatures, and membrane voltages for the pore of MthK. Direct knock-on is also observed in other potassium channels with a highly conserved selectivity filter, demonstrating the robustness of the permeation mechanism. Lastly, we investigate the charge strength dependence of permeation cycles. Our results shed light on the underlying permeation details, which are valuable in studying conduction mechanisms in potassium channels.
Topics: Potassium Channels; Cell Membrane; Molecular Dynamics Simulation; Potassium
PubMed: 37040262
DOI: 10.1021/acs.jctc.3c00061 -
Clinical Journal of the American... Jul 2014The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to... (Review)
Review
The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to maintain the "internal milieu" and allow organisms the "physiologic freedom" to move into varying environments and take in varying diets and fluids. Early ingenious, albeit rudimentary, experiments unlocked a wealth of secrets on the mechanisms involved in the formation of urine and renal handling of the gamut of electrolytes, as well as that of water, acid, and protein. Recent scientific advances have confirmed these prescient postulates such that the modern clinician is the beneficiary of a rich understanding of the nephron and the kidney's critical role in homeostasis down to the molecular level. This review summarizes those early achievements and provides a framework and introduction for the new CJASN series on renal physiology.
Topics: Acid-Base Equilibrium; Animals; Glomerular Filtration Rate; Humans; Hydrogen-Ion Concentration; Nephrons; Phosphates; Potassium; Proteins; Renal Reabsorption; Sodium; Water; Water-Electrolyte Balance
PubMed: 24789550
DOI: 10.2215/CJN.08860813 -
Science Advances Dec 2020Potassium-chloride cotransporters KCC1 to KCC4 mediate the coupled export of potassium and chloride across the plasma membrane and play important roles in cell volume...
Potassium-chloride cotransporters KCC1 to KCC4 mediate the coupled export of potassium and chloride across the plasma membrane and play important roles in cell volume regulation, auditory system function, and γ-aminobutyric acid (GABA) and glycine-mediated inhibitory neurotransmission. Here, we present 2.9- to 3.6-Å resolution structures of full-length human KCC2, KCC3, and KCC4. All three KCCs adopt a similar overall architecture, a domain-swap dimeric assembly, and an inward-facing conformation. The structural and functional studies reveal that one unexpected N-terminal peptide binds at the cytosolic facing cavity and locks KCC2 and KCC4 at an autoinhibition state. The C-terminal domain (CTD) directly interacts with the N-terminal inhibitory peptide, and the relative motions between the CTD and the transmembrane domain (TMD) suggest that CTD regulates KCCs' activities by adjusting the autoinhibitory effect. These structures provide the first glimpse of full-length structures of KCCs and an autoinhibition mechanism among the amino acid-polyamine-organocation transporter superfamily.
Topics: Cell Membrane; Chlorides; Humans; Potassium; Symporters; K Cl- Cotransporters
PubMed: 33310850
DOI: 10.1126/sciadv.abc5883 -
Metal Ions in Life Sciences 2016Alkali metals, especially sodium and potassium, are plentiful and vital in biological systems. They take on important roles in health and disease. Such roles include the...
Alkali metals, especially sodium and potassium, are plentiful and vital in biological systems. They take on important roles in health and disease. Such roles include the regulation of homeostasis, osmosis, blood pressure, electrolytic equilibria, and electric current. However, there is a limit to our present understanding; the ions have a great ability and capacity for action in health and disease, much greater than our current understanding. For the regulation of physiological homeostasis, there is a crucial regulator (renin-angiotensin system, RAS), found at both peripheral and central levels. Misregulation of the Na(+)-K(+) pump, and sodium channels in RAS are important for the understanding of disease progression, hypertension, diabetes, and neurodegenerative diseases, etc. In particular, RAS displays direct or indirect interaction important to Parkinson's disease (PD). In this chapter, the relationship between the regulation of sodium/potassium concentration and PD was sought. In addition, some recent biochemical and clinical findings are also discussed that help describe sodium and potassium in the context of traumatic brain injury (TBI). TBI is caused from the heavy striking of the head; this strongly affects ion flux in the affected tissue (brain) and damages cellular regulation systems. Thus, inappropriate concentrations of ions (hyper- and hyponatremia, and hyper- and hypokalemia) will perturb homeostasis giving rise to important and far reaching effects. These changes also impact osmotic pressure and the concentration of other metal ions, such as the calcium(II) ion.
Topics: Brain Injuries; Humans; Ion Channel Gating; Ischemia; Parkinson Disease; Potassium; Sodium
PubMed: 26860312
DOI: 10.1007/978-3-319-21756-7_16 -
The Journal of Biological Chemistry Sep 2016Regulation of enzymes through metal ion complexation is widespread in biology and underscores a physiological need for stability and high catalytic activity that likely... (Review)
Review
Regulation of enzymes through metal ion complexation is widespread in biology and underscores a physiological need for stability and high catalytic activity that likely predated proteins in the RNA world. In addition to divalent metals such as Ca, Mg, and Zn, monovalent cations often function as efficient and selective promoters of catalysis. Advances in structural biology unravel a rich repertoire of molecular mechanisms for enzyme activation by Na and K Strategies range from short-range effects mediated by direct participation in substrate binding, to more distributed effects that propagate long-range to catalytic residues. This review addresses general considerations and examples.
Topics: Catalysis; Cations, Monovalent; Enzymes; Potassium; Sodium
PubMed: 27462078
DOI: 10.1074/jbc.R116.737833 -
Physiology (Bethesda, Md.) Sep 2015Proper function of all excitable cells depends on ion homeostasis. Nowhere is this more critical than in the brain where the extracellular concentration of some ions... (Review)
Review
Proper function of all excitable cells depends on ion homeostasis. Nowhere is this more critical than in the brain where the extracellular concentration of some ions determines neurons' firing pattern and ability to encode information. Several neuronal functions depend on the ability of neurons to change their firing pattern to a rhythmic bursting pattern, whereas, in some circuits, rhythmic firing is, on the contrary, associated to pathologies like epilepsy or Parkinson's disease. In this review, we focus on the four main ions known to fluctuate during rhythmic firing: calcium, potassium, sodium, and chloride. We discuss the synergistic interactions between these elements to promote an oscillatory activity. We also review evidence supporting an important role for astrocytes in the homeostasis of each of these ions and describe mechanisms by which astrocytes may regulate neuronal firing by altering their extracellular concentrations. A particular emphasis is put on the mechanisms underlying rhythmogenesis in the circuit forming the central pattern generator (CPG) for mastication and other CPG systems. Finally, we discuss how an impairment in the ability of glial cells to maintain such homeostasis may result in pathologies like epilepsy and Parkinson's disease.
Topics: Action Potentials; Animals; Astrocytes; Brain; Calcium; Cell Communication; Central Pattern Generators; Chlorides; Epilepsy; Homeostasis; Humans; Ion Transport; Kinetics; Movement Disorders; Neurons; Periodicity; Potassium; Sodium
PubMed: 26328882
DOI: 10.1152/physiol.00023.2014 -
Journal of the American Society of... Jun 2023Rapid renal responses to ingested potassium are essential to prevent hyperkalemia and also play a central role in blood pressure regulation. Although local extracellular...
SIGNIFICANCE STATEMENT
Rapid renal responses to ingested potassium are essential to prevent hyperkalemia and also play a central role in blood pressure regulation. Although local extracellular K + concentration in kidney tissue is increasingly recognized as an important regulator of K + secretion, the underlying mechanisms that are relevant in vivo remain controversial. To assess the role of the signaling kinase mTOR complex-2 (mTORC2), the authors compared the effects of K + administered by gavage in wild-type mice and knockout mice with kidney tubule-specific inactivation of mTORC2. They found that mTORC2 is rapidly activated to trigger K + secretion and maintain electrolyte homeostasis. Downstream targets of mTORC2 implicated in epithelial sodium channel regulation (SGK1 and Nedd4-2) were concomitantly phosphorylated in wild-type, but not knockout, mice. These findings offer insight into electrolyte physiologic and regulatory mechanisms.
BACKGROUND
Increasing evidence implicates the signaling kinase mTOR complex-2 (mTORC2) in rapid renal responses to changes in plasma potassium concentration [K + ]. However, the underlying cellular and molecular mechanisms that are relevant in vivo for these responses remain controversial.
METHODS
We used Cre-Lox-mediated knockout of rapamycin-insensitive companion of TOR (Rictor) to inactivate mTORC2 in kidney tubule cells of mice. In a series of time-course experiments in wild-type and knockout mice, we assessed urinary and blood parameters and renal expression and activity of signaling molecules and transport proteins after a K + load by gavage.
RESULTS
A K + load rapidly stimulated epithelial sodium channel (ENaC) processing, plasma membrane localization, and activity in wild-type, but not in knockout, mice. Downstream targets of mTORC2 implicated in ENaC regulation (SGK1 and Nedd4-2) were concomitantly phosphorylated in wild-type, but not knockout, mice. We observed differences in urine electrolytes within 60 minutes, and plasma [K + ] was greater in knockout mice within 3 hours of gavage. Renal outer medullary potassium (ROMK) channels were not acutely stimulated in wild-type or knockout mice, nor were phosphorylation of other mTORC2 substrates (PKC and Akt).
CONCLUSIONS
The mTORC2-SGK1-Nedd4-2-ENaC signaling axis is a key mediator of rapid tubule cell responses to increased plasma [K + ] in vivo . The effects of K + on this signaling module are specific, in that other downstream mTORC2 targets, such as PKC and Akt, are not acutely affected, and ROMK and Large-conductance K + (BK) channels are not activated. These findings provide new insight into the signaling network and ion transport systems that underlie renal responses to K +in vivo .
Topics: Mice; Animals; Phosphorylation; Potassium; Epithelial Sodium Channels; Protein Serine-Threonine Kinases; Potassium, Dietary; TOR Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Immediate-Early Proteins; Mechanistic Target of Rapamycin Complex 2; Kidney; Carrier Proteins; Mice, Knockout; Ion Transport
PubMed: 36890646
DOI: 10.1681/ASN.0000000000000109 -
The Journal of General Physiology Oct 2021The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological...
The ability to discriminate between different ionic species, termed ion selectivity, is a key feature of ion channels and forms the basis for their physiological function. Members of the degenerin/epithelial sodium channel (DEG/ENaC) superfamily of trimeric ion channels are typically sodium selective, but to a surprisingly variable degree. While acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium ratio ∼10:1), ENaCs show a remarkably high preference for sodium over potassium (>500:1). This discrepancy may be expected to originate from differences in the pore-lining second transmembrane segment (M2). However, these show a relatively high degree of sequence conservation between ASICs and ENaCs, and previous functional and structural studies could not unequivocally establish that differences in M2 alone can account for the disparate degrees of ion selectivity. By contrast, surprisingly little is known about the contributions of the first transmembrane segment (M1) and the preceding pre-M1 region. In this study, we used conventional and noncanonical amino acid-based mutagenesis in combination with a variety of electrophysiological approaches to show that the pre-M1 and M1 regions of mASIC1a channels are major determinants of ion selectivity. Mutational investigations of the corresponding regions in hENaC show that these regions contribute less to ion selectivity, despite affecting ion conductance. In conclusion, our work suggests that the remarkably different degrees of sodium selectivity in ASICs and ENaCs are achieved through different mechanisms. These results further highlight how M1 and pre-M1 are likely to differentially affect pore structure in these related channels.
Topics: Acid Sensing Ion Channels; Epithelial Sodium Channels; Ions; Potassium; Sodium
PubMed: 34436511
DOI: 10.1085/jgp.202112899 -
Nucleic Acids Research Jul 2014We present a new method for analyzing ion, or molecule, distributions around helical nucleic acids and illustrate the approach by analyzing data derived from molecular...
We present a new method for analyzing ion, or molecule, distributions around helical nucleic acids and illustrate the approach by analyzing data derived from molecular dynamics simulations. The analysis is based on the use of curvilinear helicoidal coordinates and leads to highly localized ion densities compared to those obtained by simply superposing molecular dynamics snapshots in Cartesian space. The results identify highly populated and sequence-dependent regions where ions strongly interact with the nucleic and are coupled to its conformational fluctuations. The data from this approach is presented as ion populations or ion densities (in units of molarity) and can be analyzed in radial, angular and longitudinal coordinates using 1D or 2D graphics. It is also possible to regenerate 3D densities in Cartesian space. This approach makes it easy to understand and compare ion distributions and also allows the calculation of average ion populations in any desired zone surrounding a nucleic acid without requiring references to its constituent atoms. The method is illustrated using microsecond molecular dynamics simulations for two different DNA oligomers in the presence of 0.15 M potassium chloride. We discuss the results in terms of convergence, sequence-specific ion binding and coupling with DNA conformation.
Topics: Chlorides; DNA; Ions; Molecular Dynamics Simulation; Nucleic Acid Conformation; Phosphorus; Potassium
PubMed: 24906882
DOI: 10.1093/nar/gku504