Thiazolidinedione insulin sensitizers alter lipid bilayer properties and voltage-dependent sodium channel function: implications for drug discovery

Rusinova, Radda; Herold, Karl F.; Sanford, R. Lea; Greathouse, Denise V.; Hemmings, Hugh C.; Andersen, Olaf S.

doi:10.1085/jgp.201010529

Cited by 50 publications

(181 citation statements)

References 105 publications

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“…The alkylphenols are hydrophobic, with calculated octanol/water partition coefficients (expressed as cLog P) of approximately 5 , comparable with that of potent bilayer modifiers (Rusinova et al, 2011). General anesthetics have been shown to exert many, but perhaps not all, of their effects via specific interactions with ion channels (Eger et al, 2008), thereby leaving open the possibility that those that are lipophiles (such as the alkylphenols) may also alter embedded membrane protein function via interactions with the lipid bilayer (Lundbaek et al, 2010) (Fig.…”

Section: Resultsmentioning

confidence: 96%

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

Tibbs

Rowley

Sanford

et al. 2013

J Pharmacol Exp Ther

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Chronic pain after peripheral nerve injury is associated with afferent hyperexcitability and upregulation of hyperpolarizationactivated, cyclic nucleotide-regulated (HCN)-mediated I H pacemaker currents in sensory neurons. HCN channels thus constitute an attractive target for treating chronic pain. HCN channels are ubiquitously expressed; analgesics targeting HCN1-rich cells in the peripheral nervous system must spare the cardiac pacemaker current (carried mostly by HCN2 and HCN4) and the central nervous system (where all four isoforms are expressed). The alkylphenol general anesthetic propofol (2,6-diiso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery. Consequently, we hypothesized that propofol, and congeners, should be antihyperalgesic. Alkyl-substituted propofol analogs have different rank-order potencies with respect to HCN1 inhibition, GABA A receptor (GABA A -R) potentiation, and general anesthesia. Thus, 2,6-and 2,4-di-tertbutylphenol (2,6-and 2,4-DTBP, respectively) are more potent HCN1 antagonists than propofol, whereas 2,6-and 2,4-di-sec-butylphenol (2,6-and 2,4-DSBP, respectively) are less potent. In contrast, DSBPs, but not DTBPs, enhance GABA A -R function and are general anesthetics. 2,6-DTBP retained propofol's selectivity for HCN1 over HCN2-HCN4. In a peripheral nerve ligation model of neuropathic pain, 2,6-DTBP and subhypnotic propofol are antihyperalgesic. The findings are consistent with these alkylphenols exerting analgesia via non-GABA A -R targets and suggest that antagonism of central HCN1 channels may be of limited importance to general anesthesia. Alkylphenols are hydrophobic, and thus potential modifiers of lipid bilayers, but their effects on HCN channels are due to direct drug-channel interactions because they have little bilayer-modifying effect at therapeutic concentrations. The alkylphenol antihyperalgesic target may be HCN1 channels in the damaged peripheral nervous system.

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Section: Resultsmentioning

confidence: 96%

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

Tibbs

Rowley

Sanford

et al. 2013

J Pharmacol Exp Ther

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“…S1). We note that the DG and CA1 differ substantially in terms of neurogenerative potential, cell type populations, and resistance to oxidative stress, all which may significantly affect downstream responses to PPAR agonism (Harrington et al, 2007; Jahrling et al, 2014; Nenov et al, 2014; Rusinova et al, 2011). Analysis of electrophysiological parameters from previously collected studies support an RSG-dependent effect on action potential time to rise and time to decay half-amplitude opposing Tg2576-dependent alterations in the action potential waveform (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…Dysregulation of the ERK-MAPK signaling pathway that subserves hippocampus-dependent cognition (Denner et al, 2012; Ahi et al, 2004; Atkins et al, 1998; Sweatt, 2004; McGaugh, 2000; Jahrling et al, 2014), the presynaptic VAMP-2 glutamate release machinery (Nenov et al, 2014), and voltage-gated ion channels (Nenov et al, 2015) may mediate the effect of RSG treatment on granule neuron function, but details of how PPARγ–agonism affects excitability in ion channel complexes are lacking. Because voltage-gated ion channels are the fundamental unit of excitability in the neuron, investigating how RSG treatment affects ion channel proteins may identify critical nodes in downstream pathways of Aβ pathology and provide useful information for therapeutic strategies (Rusinova et al, 2011; Imbrici et al, 2016; Catterall, 2012). …”

Section: Introductionmentioning

confidence: 99%

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

Hsu

Wildburger

Haidacher

et al. 2017

Experimental Neurology

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Background Cognitive impairment in humans with Alzheimer's disease (AD) and in animal models of Aβ-pathology can be ameliorated by treatments with the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, such as rosiglitazone (RSG). Previously, we demonstrated that in the Tg2576 animal model of AD, RSG treatment rescued cognitive deficits and reduced aberrant activity of granule neurons in the dentate gyrus (DG), an area critical for memory formation. Methods We used a combination of mass spectrometry, confocal imaging, electrophysiology and split-luciferase assay and in vitro phosphorylation and Ingenuity Pathway Analysis. Results Using an unbiased, quantitative nano-LC-MS/MS screening, we searched for potential molecular targets of the RSG-dependent rescue of DG granule neurons. We found that S226 phosphorylation of fibroblast growth factor 14 (FGF14), an accessory protein of the voltage-gated Na+ (Nav) channels required for neuronal firing, was reduced in Tg2576 mice upon treatment with RSG. Using confocal microscopy, we confirmed that the Tg2576 condition decreased PanNav channels at the AIS of the DG, and that RSG treatment of Tg2576 mice reversed the reduction in PanNav channels. Analysis from previously published data sets identified correlative changes in action potential kinetics in RSG-treated T2576 compared to untreated and wildtype controls. In vitro phosphorylation and mass spectrometry confirmed that the multifunctional kinase GSK–3β, a downstream target of insulin signaling highly implicated in AD, phosphorylated FGF14 at S226. Assembly of the FGF14:Nav1.6 channel complex and functional regulation of Nav1.6-mediated currents by FGF14 was impaired by a phosphosilent S226A mutation. Bioinformatics pathway analysis of mass spectrometry and biochemistry data revealed a highly interconnected network encompassing PPARγ, FGF14, SCN8A (Nav 1.6), and the kinases GSK–3 β, casein kinase 2β, and ERK1/2. Conclusions These results identify FGF14 as a potential PPARγ-sensitive target controlling Aβ-induced dysfunctions of neuronal activity in the DG underlying memory loss in early AD.

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“…A statistical test of linearity is problematic, however. Except for the LPLs, ΔΔG ‡ 1 is determined from measured changes in k 1 , whereas ΔΔG 0 is determined from measured changes in k 1 and k −1 (40,52,(54)(55)(56)(57). So, k 1 contributes in the determination of both ΔΔG ‡ 1 and ΔΔG 0 .…”

Section: Discussionmentioning

confidence: 99%

Linear rate-equilibrium relations arising from ion channel-bilayer energetic coupling

Greisen

Lum

Ashrafuzzaman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Linear rate-equilibrium (RE) relations, also known as linear free energy relations, are widely observed in chemical reactions, including protein folding, enzymatic catalysis, and channel gating. Despite the widespread occurrence of linear RE relations, the principles underlying the linear relation between changes in activation and equilibrium energy in macromolecular reactions remain enigmatic. When examining amphiphile regulation of gramicidin channel gating in lipid bilayers, we noted that the gating process could be described by a linear RE relation with a simple geometric interpretation. This description is possible because the gating process provides a well-understood reaction, in which structural changes in a bilayer-embedded model protein can be studied at the singlemolecule level. It is thus possible to obtain quantitative information about the energetics of the reaction transition state and its position on a spatial coordinate. It turns out that the linear RE relation for the gramicidin monomer-dimer reaction can be understood, and the quantitative relation between changes in activation energy and equilibrium energy can be interpreted, by considering the effects of amphiphiles on the changes in bilayer elastic energy associated with channel gating. We are not aware that a similar simple mechanistic explanation of a linear RE relation has been provided for a chemical reaction in a macromolecule. RE relations generally should be useful for examining how amphiphile-induced changes in bilayer properties modulate membrane protein folding and function, and for distinguishing between direct (e.g., due to binding) and indirect (bilayer-mediated) effects.Brønsted | linear free energy relationships | phi value | bilayer elasticity I t is a common observation that manipulations that alter the energetics of a reaction:alter the rate constants (k 1 and k −1 ) and equilibrium constant (K eq ¼ k 1 ∕k −1 ), such that lnfk 1 g is a linear function of lnfK eq g. This linearity is interpreted to mean that, for a series of manipulations of the reaction, the activation free energy (ΔG ‡ ) varies as a linear function of the equilibrium free energy (ΔG 0 ):where a is a slope factor and b a constant (1-3). Such linear relations, known as linear rate-equilibrium (RE) relations (4), linear free energy relations (5), or linear rate-equilibrium free energy relations (6), have been observed and studied since the early 1900s. First observed in acid-based reactions (7-9), they have been identified in a wide range of reactions (1-3). Leffler proposed, based on studies of covalent reactions, that the slope factor a (Eq. 2) identifies the position of the transition state on a reaction coordinate, where S and P are positioned at 0 and 1, respectively (5). Marcus and coworkers deduced the principles underlying linear RE relations in electron transfer processes using a model in which the transfer is described as a one-step transition between two harmonic energy wells (10, 11). Fersht and coworkers used linear RE relations associated with p...

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Thiazolidinedione insulin sensitizers alter lipid bilayer properties and voltage-dependent sodium channel function: implications for drug discovery

Cited by 50 publications

References 105 publications

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

Linear rate-equilibrium relations arising from ion channel-bilayer energetic coupling

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