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  1. Article ; Online: Glucokinase Inhibition: A Novel Treatment for Diabetes?

    Remedi, Maria S / Nichols, Colin G

    Diabetes

    2024  Volume 72, Issue 2, Page(s) 170–174

    Abstract: Chronic hyperglycemia increases pancreatic β-cell metabolic activity, contributing to glucotoxicity-induced β-cell failure and loss of functional β-cell mass, potentially in multiple forms of diabetes. In this perspective we discuss the novel paradoxical ...

    Abstract Chronic hyperglycemia increases pancreatic β-cell metabolic activity, contributing to glucotoxicity-induced β-cell failure and loss of functional β-cell mass, potentially in multiple forms of diabetes. In this perspective we discuss the novel paradoxical and counterintuitive concept of inhibiting glycolysis, particularly by targeted inhibition of glucokinase, the first enzyme in glycolysis, as an approach to maintaining glucose sensing and preserving functional β-cell mass, thereby improving insulin secretion, in the treatment of diabetes.
    MeSH term(s) Humans ; Glucokinase/metabolism ; Insulin/metabolism ; Diabetes Mellitus/drug therapy ; Diabetes Mellitus/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/metabolism ; Glucose/metabolism
    Chemical Substances Glucokinase (EC 2.7.1.2) ; Insulin ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2024-02-21
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 80085-5
    ISSN 1939-327X ; 0012-1797
    ISSN (online) 1939-327X
    ISSN 0012-1797
    DOI 10.2337/db22-0731
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Personalized Therapeutics for K

    Nichols, Colin G

    Annual review of pharmacology and toxicology

    2022  Volume 63, Page(s) 541–563

    Abstract: Ubiquitously expressed throughout the body, ATP-sensitive potassium ( ... ...

    Abstract Ubiquitously expressed throughout the body, ATP-sensitive potassium (K
    MeSH term(s) Humans ; Potassium Channels, Inwardly Rectifying/genetics ; Potassium Channels, Inwardly Rectifying/metabolism ; Sulfonylurea Receptors/genetics ; Sulfonylurea Receptors/metabolism ; Mutation ; Adenosine Triphosphate/metabolism ; Adenosine Triphosphate/pharmacology
    Chemical Substances Potassium Channels, Inwardly Rectifying ; Sulfonylurea Receptors ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2022-09-28
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 196587-6
    ISSN 1545-4304 ; 0362-1642
    ISSN (online) 1545-4304
    ISSN 0362-1642
    DOI 10.1146/annurev-pharmtox-051921-123023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Seeing spermine blocking of K+ ion movement through inward rectifier Kir2.2 channels.

    Lee, Sun-Joo / Nichols, Colin G

    The Journal of general physiology

    2022  Volume 155, Issue 2

    Abstract: Inwardly rectifier potassium (Kir) channels are a major potassium channel sub-class whose function is regulated by ligand-dependent gating and highly voltage-dependent block by polyamines. With molecular dynamics simulations over previously unattainable ... ...

    Abstract Inwardly rectifier potassium (Kir) channels are a major potassium channel sub-class whose function is regulated by ligand-dependent gating and highly voltage-dependent block by polyamines. With molecular dynamics simulations over previously unattainable timescales, Jogini et al. (J. Gen. Physiol. https://doi.org/10.1085/jgp.202213085) provide unprecedented visualization of K+ conduction through open Kir2.2 channels and of the molecular details of channel block by spermine.
    MeSH term(s) Spermine/pharmacology ; Ion Channel Gating ; Polyamines/pharmacology ; Potassium Channel Blockers/pharmacology ; Potassium/pharmacology
    Chemical Substances Spermine (2FZ7Y3VOQX) ; Polyamines ; Potassium Channel Blockers ; Potassium (RWP5GA015D)
    Language English
    Publishing date 2022-12-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 3118-5
    ISSN 1540-7748 ; 0022-1295
    ISSN (online) 1540-7748
    ISSN 0022-1295
    DOI 10.1085/jgp.202213144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Blockade of TRPV channels by intracellular spermine.

    Maksaev, Grigory / Yuan, Peng / Nichols, Colin G

    The Journal of general physiology

    2023  Volume 155, Issue 5

    Abstract: The Vanilloid thermoTRP (TRPV1-4) subfamily of TRP channels are involved in thermoregulation, osmoregulation, itch and pain perception, (neuro)inflammation and immune response, and tight control of channel activity is required for perception of noxious ... ...

    Abstract The Vanilloid thermoTRP (TRPV1-4) subfamily of TRP channels are involved in thermoregulation, osmoregulation, itch and pain perception, (neuro)inflammation and immune response, and tight control of channel activity is required for perception of noxious stimuli and pain. Here we report voltage-dependent modulation of each of human TRPV1, 3, and 4 by the endogenous intracellular polyamine spermine. As in inward rectifier K channels, currents are blocked in a strongly voltage-dependent manner, but, as in cyclic nucleotide-gated channels, the blockade is substantially reduced at more positive voltages, with maximal blockade in the vicinity of zero voltage. A kinetic model of inhibition suggests two independent spermine binding sites with different affinities as well as different degrees of polyamine permeability in TRPV1, 3, and 4. Given that block and relief occur over the physiological voltage range of action potentials, voltage-dependent polyamine block may be a potent modulator of TRPV-dependent excitability in multiple cell types.
    MeSH term(s) Humans ; Spermine/pharmacology ; Spermine/metabolism ; Polyamines/pharmacology ; Polyamines/metabolism ; Action Potentials/physiology ; Potassium Channels, Inwardly Rectifying/metabolism
    Chemical Substances Spermine (2FZ7Y3VOQX) ; Polyamines ; Potassium Channels, Inwardly Rectifying
    Language English
    Publishing date 2023-03-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3118-5
    ISSN 1540-7748 ; 0022-1295
    ISSN (online) 1540-7748
    ISSN 0022-1295
    DOI 10.1085/jgp.202213273
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Oxidation Driven Reversal of PIP

    Lee, Sun-Joo / Maeda, Shoji / Gao, Jian / Nichols, Colin G

    Function (Oxford, England)

    2023  Volume 4, Issue 3, Page(s) zqad016

    Abstract: Physiological activity of G protein gated inward rectifier K ...

    Abstract Physiological activity of G protein gated inward rectifier K
    MeSH term(s) G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics ; GTP-Binding Proteins/metabolism ; Ligands ; Oxidation-Reduction
    Chemical Substances G Protein-Coupled Inwardly-Rectifying Potassium Channels ; GTP-Binding Proteins (EC 3.6.1.-) ; Ligands ; KCNJ6 protein, human
    Language English
    Publishing date 2023-04-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2633-8823
    ISSN (online) 2633-8823
    DOI 10.1093/function/zqad016
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  6. Article ; Online: Bridging Personal and Population in Excitability Diseases: Will Studies of Rare Diseases Bring Generalizable Mechanisms From Monogenic Channelopathies?

    Nichols, Colin G / McClenaghan, Conor

    Function (Oxford, England)

    2022  Volume 3, Issue 1, Page(s) zqab072

    MeSH term(s) Humans ; Channelopathies/genetics ; Rare Diseases/genetics ; Mental Disorders
    Language English
    Publishing date 2022-01-04
    Publishing country England
    Document type Journal Article
    ISSN 2633-8823
    ISSN (online) 2633-8823
    DOI 10.1093/function/zqab072
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  7. Article ; Online: K

    Davis, Michael J / Kim, Hae Jin / Nichols, Colin G

    American journal of physiology. Cell physiology

    2022  Volume 323, Issue 4, Page(s) C1018–C1035

    Abstract: ... ...

    Abstract K
    MeSH term(s) Adenosine Triphosphate ; Cardiomegaly/metabolism ; Humans ; Hypertrichosis/metabolism ; KATP Channels/genetics ; KATP Channels/metabolism ; Osteochondrodysplasias/metabolism
    Chemical Substances KATP Channels ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2022-07-04
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00137.2022
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  8. Article ; Online: Kir6.1 and SUR2B in Cantú syndrome.

    McClenaghan, Conor / Nichols, Colin G

    American journal of physiology. Cell physiology

    2022  Volume 323, Issue 3, Page(s) C920–C935

    Abstract: Kir6.1 and SUR2 are subunits of ATP-sensitive potassium ( ... ...

    Abstract Kir6.1 and SUR2 are subunits of ATP-sensitive potassium (K
    MeSH term(s) Adenosine Triphosphate ; Animals ; Cardiomegaly/genetics ; Humans ; Hypertrichosis/genetics ; KATP Channels/genetics ; Mice ; Osteochondrodysplasias/genetics ; Sulfonylurea Receptors/genetics
    Chemical Substances KATP Channels ; Sulfonylurea Receptors ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2022-07-25
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00154.2022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Pore-forming transmembrane domains control ion selectivity and selectivity filter conformation in the KirBac1.1 potassium channel.

    Matamoros, Marcos / Nichols, Colin G

    The Journal of general physiology

    2021  Volume 153, Issue 5

    Abstract: Potassium (K+) channels are membrane proteins with the remarkable ability to very selectively conduct K+ ions across the membrane. High-resolution structures have revealed that dehydrated K+ ions permeate through the narrowest region of the pore, formed ... ...

    Abstract Potassium (K+) channels are membrane proteins with the remarkable ability to very selectively conduct K+ ions across the membrane. High-resolution structures have revealed that dehydrated K+ ions permeate through the narrowest region of the pore, formed by the backbone carbonyls of the signature selectivity filter (SF) sequence TxGYG. However, the existence of nonselective channels with similar SF sequences, as well as effects of mutations in other regions on selectivity, suggest that the SF is not the sole determinant of selectivity. We changed the selectivity of the KirBac1.1 channel by introducing mutations at residue I131 in transmembrane helix 2 (TM2). These mutations increase Na+ flux in the absence of K+ and introduce significant proton conductance. Consistent with K+ channel crystal structures, single-molecule FRET experiments show that the SF is conformationally constrained and stable in high-K+ conditions but undergoes transitions to dilated low-FRET states in high-Na+/low-K+ conditions. Relative to wild-type channels, I131M mutants exhibit marked shifts in the K+ and Na+ dependence of SF dynamics to higher K+ and lower Na+ concentrations. These results illuminate the role of I131, and potentially other structural elements outside the SF, in controlling ion selectivity, by suggesting that the physical interaction of these elements with the SF contributes to the relative stability of the constrained K+-induced SF configuration versus nonselective dilated conformations.
    MeSH term(s) Potassium/metabolism ; Potassium Channels/genetics ; Potassium Channels/metabolism ; Protein Domains ; Protons ; Sodium/metabolism
    Chemical Substances Potassium Channels ; Protons ; Sodium (9NEZ333N27) ; Potassium (RWP5GA015D)
    Language English
    Publishing date 2021-03-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3118-5
    ISSN 1540-7748 ; 0022-1295
    ISSN (online) 1540-7748
    ISSN 0022-1295
    DOI 10.1085/jgp.202012683
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  10. Article ; Online: ATP-Sensitive Potassium Channels in Hyperinsulinism and Type 2 Diabetes: Inconvenient Paradox or New Paradigm?

    Nichols, Colin G / York, Nathaniel W / Remedi, Maria S

    Diabetes

    2022  Volume 71, Issue 3, Page(s) 367–375

    Abstract: Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of ... ...

    Abstract Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.
    MeSH term(s) Animals ; Blood Glucose ; Calcium/pharmacology ; Congenital Hyperinsulinism/genetics ; Congenital Hyperinsulinism/physiopathology ; Diabetes Mellitus, Type 2/physiopathology ; Humans ; Insulin Resistance ; Insulin Secretion/genetics ; Insulin Secretion/physiology ; KATP Channels/genetics ; KATP Channels/physiology ; Mice ; Mice, Knockout ; Mutation ; Potassium Channels, Inwardly Rectifying/genetics ; Potassium Channels, Inwardly Rectifying/physiology ; Sulfonylurea Receptors/genetics ; Sulfonylurea Receptors/physiology
    Chemical Substances ABCC8 protein, human ; Abcc8 protein, mouse ; Blood Glucose ; KATP Channels ; Kir6.2 channel ; Potassium Channels, Inwardly Rectifying ; Sulfonylurea Receptors ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2022-02-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 80085-5
    ISSN 1939-327X ; 0012-1797
    ISSN (online) 1939-327X
    ISSN 0012-1797
    DOI 10.2337/db21-0755
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