Department of Cellular Neurophysiology (DCN) .Department of Cellular Neurophysiology (DCN) Report

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  • Department of Cellular Neurophysiology (DCN)

    Report on the scientific activity of the team in 20102014

    Ladislav Vyklick, MD, PhD., DSc. (Head of the Department)

    http://www.fgu.cas.cz/en/departments/cellular-neurophysiology

  • NEUROPHYSIOLOGY CARDIOVASCULAR PHYSIOLOGY

    METABOLISM

    System level

    - Circadian rhythms - Memory - Epilepsy - Alzheimers disease - Pain - Schizophrenia

    - Central and peripheral blood pressure control

    - Regulation of embryonic cardiac output

    - Pathophysiology of heart failure

    - Neurohumoral control - Energy expenditure

    - Glucose homeostasis

    - Nutritional interventions

    - Metabolic syndrome - Biomarkers

    Cellular level

    - Synaptic transmission - Neuromodulation - Nociception - Ion channels:

    NMDA, TRP, nicotinic,

    purinergic - Metabotropic receptors - Secretion of pituitary

    hormones

    - Calcium influx and calcium sensitization in contractility of resistance arteries

    - Calcium transients and ion channels

    - Gap junctional coupling

    - Isolated cardiac myocytes

    - Cell proliferation in cardiac growth and regeneration

    - Intracellular signalling - Mitochondrial

    (dys)function - Membrane biophysics

    Molecular level

    - Receptor structure- function

    - Gene and protein expression

    - Adrenergic receptor number regulation

    - Mitochondrial membrane potential

    - RhoA/Rho kinase pathway in calcium sensitization

    - Transport proteins

    - Reactive oxygen species

    - Structure of signalling proteins

    Department of Cellular Neurophysiology (DCN)

    Department of Cellular Neurophysiology IP CAS 2

  • The goal of our research is to:

    comprehend the relationship between the structure and function of ion channels, characterize the actions of pharmacologically active substances, contribute to the understanding of molecular processes involved in neurodegeneration, schizophrenia

    and nociception where ionotropic glutamate receptors, TRP channels, nicotinic type of acetylcholine receptors are involved.

    Genetic

    Structural functional

    Trafficking

    Quality of the results and share in their aquisition: Main research activities

    Our research is :

    Hypothesis based on model predictions Quantitative Methodologically advanced:

    Patch clamp technique: with fast application of

    solutions and controlled temperature PCR based methods Biochemical methods Confocal /immunofluorescence/FRET microscopy Molecular modeling and structural bioinformatics In vitro cellular models and recombinant receptors

    Ligand-gated ion channels

    Department of Cellular Neurophysiology IP CAS 3

  • Quality of the results: Structural overall quality of publications - Phase I

    Corresponding 63%

    Non-corresponding 37%

    Corresponding 55%

    Non-corresponding 45%

    Nu

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    Nu

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    ub

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    Quality profile (evaluated outputs 16)

    Quality of outputs by journal ranking (total number for bibliometry 42/58)

    Department of Cellular Neurophysiology IP CAS 4

  • Determinants of voltage-dependent gating

    S4 S5

    Mechanism for camphor activation and desensitization of TRPV1

    Domains involved in Ca2+ and PIP2 regulation (A1, V1)

    Viktorie Vlachov

    Quality of the results: Structural functional studies on TRP channels. Molecular basis of multimodal regulation of nociceptive TRP channels. TRPV1,

    TRPV3, TRPA1

    Department of Cellular Neurophysiology IP CAS 5

  • Determinants of voltage-dependent gating

    S4 S5

    Mechanism for camphor activation and desensitization of TRPV1

    Domains involved in Ca2+ and PIP2 regulation (A1, V1)

    Viktorie Vlachov

    Zma et al. (2015) Neuropharmacology 93, 294-307. Witschas et al. (2015) BBABiomembranes 1848, 1147-1156. Boukalova et al. (2013) BBAMol. Cell Res. 1833(3), 520-528. Vetter et al. (2013) J. Neurosci. 33, 16627-16641. Marsakova et al. (2012) Anesthesiology 116, 903-917. Sura et al. (2012) J. Biol. Chem. 287, 18067-18077. Vetter et al. (2012) EMBO J. 31, 3795-3808. Samad et al. (2011) Biochemical J. 433, 197-204. Boukalova et al. (2010) J. Biol. Chem. 285, 41455-41462. Hot Topic Issue: Vlachova, Guest Editor, (2011) Curr. Pharm. Biotechnol. 12, 1: TRP Channels: From Understanding to Action

    Quality of the results: Structural functional studies on TRP channels. Molecular basis of multimodal regulation of nociceptive TRP channels.

    TRPV1, TRPV3, TRPA1

    Department of Cellular Neurophysiology IP CAS 6

  • 20

    0 p

    A

    1 s

    100 M ACh

    0.5 s 1 M Lob

    2 s 1 M Lob

    5 s 1 M Lob

    50

    pA

    1 s

    5 s

    50

    0 p

    A

    3 M ACh

    0.1 M Lob

    0.3 M Lob

    1 M Lob

    3 M Lob

    10 M Lob

    30 M Lob

    Lobeline has been used as an emetic, respiratory stimulant and nicotine addiction cessation agent despite the mechanism(s) of its action being unclear.

    Lobeline inhibits responses to high concentration of acetylcholine but potentiates

    responses to low concentration of acetylcholine in 42 neuronal nicotinic receptors.

    Muscle nicotinic receptors are inhibited by lobeline.

    Jan Krek

    Quality of the results: Structural functional studies on AChR. Modulation of nicotinic receptors by plant alkaloid lobeline

    .

    Department of Cellular Neurophysiology IP CAS 7

  • 20

    0 p

    A

    1 s

    100 M ACh

    0.5 s 1 M Lob

    2 s 1 M Lob

    5 s 1 M Lob

    50

    pA

    1 s

    5 s

    50

    0 p

    A

    3 M ACh

    0.1 M Lob

    0.3 M Lob

    1 M Lob

    3 M Lob

    10 M Lob

    30 M Lob

    Lobeline inhibits responses to high concentration of acetylcholine but potentiates responses to low concentration of acetylcholine in a4b2 neuronal nicotinic receptors. Lobeline has been used for treatment of nicotine addiction.

    H. Krek/F. Vyskoil - bilateral experimental cooperation with prof. E. E. Nikolsky and prof. E. A. Bukharaeva - Kazan branch of Russian Academy of Sciences and Kazan Medical University in in studying mechanisms of cholinergic transmission: Khuzakhmetova et al., Int J Dev Neurosci 34: 9, (2014) Lindovsky et al., Eur J Pharmacol 688: 22, (2012) Petrov et al., Br J Pharmacol 163: 732, (2011) Volkov et al., Comp Biochem Physiol A 158: 520, (2011)

    Jan Krek

    Kaniakova et al. Eur. J Pharmacol 658 (2011) 108-113 Kaniakova et al. Eur. J. Pharmacol 738 (2014) 352-359

    Quality of the results: Structural functional studies on AChR. Modulation of nicotinic receptors by plant alkaloid lobeline

    .

    Department of Cellular Neurophysiology IP CAS 8

  • Extracellular channel vestibule THE SITE

    90

    Open conformation of the NMDA receptor channel

    Extracellular vestibule

    Steroids

    Pregnanolone sulfate (PA-S)

    Patch-clamp technique, Immunofluorescence, Mutagenesis, Molecular modeling and structural bioinformatics

    Quality of the results: Structural functional studies on NMDAR. Steroid inhibition of NMDAR channels.

    Department of Cellular Neurophysiology IP CAS 9

  • Extracellular channel vestibule THE SITE

    90

    Open conformation of the NMDA receptor channel

    Mem

    bra

    ne

    Extracellular vestibule

    Steroids

    Pregnanolon sulfate (PA-S)

    Patch clamp technique, Immunofluorescence, Mutagenesis, Molecular modeling and structural bioinformatics

    Papers: Korinek et al., Neuroscience 165: 736, (2010) Borovska et al., British journal of pharmacology 166: 1069, (2012) Vidrna et al., Steroids 76: 1043, (2011) Stastna et al., Steroids 74: 256, (2009) Kapras et al., Steroids 77: 282, (2012) Cerny et al., Steroids 77: 1233, (2012) Rambousek et al., Neuropharmacology 61: 61, (2011) Korinek et al., Steroids 76: 1409, (2011) Vales et al., Behavioral brain research 235: 82, (2012) Kudova et. al Journal of medicinal chemistry 58:5950-5966 (2015) Vyklicky et al., Scientific reports 5:10935 (2015)

    Book Chapter: Vyklicky et al., Analysis of whole-cell NMDAR currents, Springer Business + Science Media Series, editor: Wolfgang Walz; Ionotropic Glutamate Receptor Technologies, editor: Gabriela K Popescu

    Patents: 1. Czech Patent (UPV) No.: 303037: Pregnanolone derivatives substituted in position 3alpha, process for their

    preparation and use (Chodounska et al., CZ patent No. 303037, 2012). 2. Czech Patent (UPV) No.: 303443: Pregnanolone derivatives substituted in position 3alpha with cationic

    group, process of their preparation, their use and composition containing them (Chodounsk