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Front. Cell. Neurosci. 2017 11:226. doi: 10.3389/fncel.2017.00226

Receptor Mechanisms Mediating the Pro-Nociceptive Action of Hydrogen Sulfide in Rat Trigeminal Neurons and Meningeal Afferents. [link]

Kseniya KorolevaAlsu MustafinaAleksey YakovlevAnton HermannRashid Giniatullin and Guzel Sitdikova

Hydrogen sulfide (H2S), a well-established member of the gasotransmitter family, is involved in a variety of physiological functions, including pro-nociceptive action in the sensory system. Although several reports have shown that H2S activates sensory neurons, the molecular targets of H2S action in trigeminal (TG) nociception, implicated in migraine, remains controversial. In this study, using suction electrode recordings, we investigate the effect of the H2S donor, sodium hydrosulfide (NaHS), on nociceptive firing in rat meningeal TG nerve fibers. The effect of NaHS was also explored with patch-clamp and calcium imaging techniques on isolated TG neurons. NaHS dramatically increased the nociceptive firing in TG nerve fibers. This effect was abolished by the TRPV1 inhibitor capsazepine but was partially prevented by the TRPA1 blocker HC 030031. In a fraction of isolated TG neurons, NaHS transiently increased amplitude of capsaicin-induced currents. Moreover, NaHS by itself induced inward currents in sensory neurons, which were abolished by the TRPV1 inhibitor capsazepine suggesting involvement of TRPV1 receptors. In contrast, the inhibitor of TRPA1 receptors HC 030031 did not prevent the NaHS-induced currents. Imaging of a large population of TG neurons revealed that NaHS induced calcium transients in 41% of tested neurons. Interestingly, this effect of NaHS in some neurons was inhibited by the TRPV1 antagonist capsazepine whereas in others it was sensitive to the TRPA1 blocker HC 030031. Our data suggest that both TRPV1 and TRPA1 receptors play a role in the pro-nociceptive action of NaHS in peripheral TG nerve endings in meninges and in somas of TG neurons. We propose that activation of TRPV1 and TRPA1 receptors by H2S during neuro-inflammation conditions contributes to the nociceptive firing in primary afferents underlying migraine pain.

BioNanoSci. - 2017. - 7(1). - pp. 67-69. - DOI 10.1007/s12668-016-0288-8

The Influence of Hindlimb Unloading on Bone and Muscle Tissues in Rat Model /

V. Baltina, N.F. Ahmetov, O.A. Sachenkov, A.O. Fedyanin, I.A. Lavrov 

Numerous results indicate on interactions between muscles and bones. Thus, mechanical, genetic, endocrine, and age-related factors influence both tissues at the same time. Nevertheless, the details of physiological mechanisms of interaction between muscles and bones are still unclear. The purpose of this study was to evaluate the changes in low extremity muscles and bones during gravitational hindlimb unloading in rats. After hindlimb unloading during 7, 14, 21, and 30 days, muscles from the low extremities were collected and measured to estimate the muscle weight and perform cross-sectional analysis. Femoral bones were collected in order to evaluate weight, density, and geometrical parameters of the bone. Additionally, a test with a three-point bending was carried out to evaluate biomechanical bone properties. Results show that loss of muscle weight can be observed already at 1 week of hindlimb unloading with the maximum changes at 14 days. Changes in bone tissue showed the maximum loss of bone weight at 21 day. By 30 days of unloading, the density and rigidity of a bone were decreased; however, the most profound changes were observed in reduction of bone durability. These data support a hypothesis that the atrophy of skeletal muscles may promote the subsequent bone deterioration.

FEBS Lett. 2016 Oct;590(19):3375-3384. doi: 10.1002/1873-3468.12381. Epub 2016 Sep 15.

Homocysteine augments BK channel activity and decreases exocytosis of secretory granules in rat GH3 cells. [link]

Gaifullina AS, Yakovlev AV, Mustafina AN, Weiger TM, Hermann A, Sitdikova GF


In this study, we investigated the effects of L-homocysteine (Hcy) on maxi calcium-activated potassium (BK) channels and on exocytosis of secretory granules in GH3 rat pituitary-derived cells. A major finding of our study indicates that short-term application of Hcy increased the open probability of oxidized BK channels in inside-out recordings. Whole-cell recordings show that extracellular Hcy also augmented BK currents during long-term application. Furthermore, Hcy decreased the exocytosis of secretory granules. This decrease was partially prevented by the BK channel inhibitor paxilline and fully prevented by N-acetylcysteine, a reactive oxygen species scavenger. Taken together, our data show that elevation of cellular Hcy level induces oxidative stress, increases BK channel activity, and decreases exocytosis of secretory granules. These findings may provide insight into some of the developmental impairments and neurotoxicity associated with Hyperhomocysteinemia (HHcy), a disease arising due to abnormally elevated levels of Hcy in the plasma.

Neuroscience, Volume 340, 6 January 2017, Pages 153-165, ISSN 0306-4522, http://dx.doi.org/10.1016/j.neuroscience.2016.10.051. [link]

 Hydrogen sulfide inhibits giant depolarizing potentials and abolishes epileptiform activity of neonatal rat hippocampal slices. 

Aleksey V. Yakovlev, Evgeniya D. Kurmasheva, Rashid Giniatullin, Ilgam Khalilov, Guzel F. Sitdikova,


Hydrogen sulfide (H2S) is an endogenous gasotransmitter with neuroprotective properties that participates in the regulation of transmitter release and neuronal excitability in various brain structures. The role of H2S in the growth and maturation of neural networks however remains unclear. The aim of the present study is to reveal the effects of H2S on neuronal spontaneous activity relevant to neuronal maturation in hippocampal slices of neonatal rats. Sodium hydrosulfide (NaHS) (100 μM), a classical donor of H2S produced a biphasic effect with initial activation and subsequent concentration-dependent suppression of network-driven giant depolarizing potentials (GDPs) and neuronal spiking activity. Likewise, the substrate of H2S synthesis l-cysteine (1 mM) induced an initial increase followed by an inhibition of GDPs and spiking activity. Our experiments indicate that the increase in initial discharge activity by NaHS is evoked by neuronal depolarization which is partially mediated by a reduction of outward K+ currents. The subsequent decrease in the neuronal activity by H2S appears to be due to the rightward shift of activation and inactivation of voltage-gated Na+ currents, thus preventing network activity. NaHS also reduced N-methyl-d-aspartate (NMDA)-mediated currents, without essential effect on AMPA/kainate or GABAA-mediated currents. Finally, H2S abolished the interictal-like events induced by bicuculline. In summary, our results suggest that through the inhibitory action on voltage-gated Na+ channels and NMDA receptors, H2S prevents the enhanced neuronal excitability typical to early hippocampal networks.

Brain Research, Volume 1648, Part A, 1 October 2016, Pages 214-223, ISSN 0006-8993, http://dx.doi.org/10.1016/j.brainres.2016.07.020. [link]

Spatial patterns and cell surface clusters in perineuronal nets

Nikita Arnst, Svetlana Kuznetsova, Nikita Lipachev, Nurislam Shaikhutdinov, Anastasiya Melnikova, Mikhail Mavlikeev, Pavel Uvarov, Tatyana V. Baltina, Heikki Rauvala, Yuriy N. Osin, Andrey P. Kiyasov, Mikhail Paveliev,


Abstract Perineuronal nets (PNN) ensheath GABAergic and glutamatergic synapses on neuronal cell surface in the central nervous system (CNS), have neuroprotective effect in animal models of Alzheimer disease and regulate synaptic plasticity during development and regeneration. Crucial insights were obtained recently concerning molecular composition and physiological importance of PNN but the microstructure of the network remains largely unstudied. Here we used histochemistry, fluorescent microscopy and quantitative image analysis to study the PNN structure in adult mouse and rat neurons from layers IV and VI of the somatosensory cortex. Vast majority of meshes have quadrangle, pentagon or hexagon shape with mean mesh area of 1.29 ?m2 in mouse and 1.44 ?m2 in rat neurons. We demonstrate two distinct patterns of chondroitin sulfate distribution within a single mesh – with uniform (nonpolar) and node-enriched (polar) distribution of the Wisteria floribunda agglutinin-positive signal. Vertices of the node-enriched pattern match better with local maxima of chondroitin sulfate density as compared to the uniform pattern. PNN is organized into clusters of meshes with distinct morphologies on the neuronal cell surface. Our findings suggest the role for the PNN microstructure in the synaptic transduction and plasticity.

Sitdikova GF, Fuchs R, Kainz V, Weiger TM and Hermann A Phosphorylation of BK channels modulates the sensitivity to hydrogen sulfide (H2S). Front. Physiol 2014. 5:431. [Link]


     Gases, such as nitric oxide (NO), carbon monoxide (CO), or hydrogen sulfide (H2S), termed gasotransmitters, play an increasingly important role in understanding of how electrical signaling of cells is modulated. H2S is well-known to act on various ion channels and receptors. In a previous study we reported that H2S increased calcium-activated potassium (BK) channel activity. AIMS: The goal of the present study is to investigate the modulatory effect of BK channel phosphorylation on the action of H2S on the channel as well as to recalculate and determine the H2S concentrations in aqueous sodium hydrogen sulfide (NaHS) solutions. METHODS:Single channel recordings of GH3, GH4, and GH4 STREX cells were used to analyze channel open probability, amplitude, and open dwell times. H2S was measured with an anion selective electrode. RESULTS:The concentration of H2S produced from NaHS was recalculated taking pH, temperature salinity of the perfusate, and evaporation of H2S into account. The results indicate that from a concentration of 300 μM NaHS, only 11-13%, i.e., 34-41 μM is effective as H2S in solution. GH3, GH4, and GH4 STREX cells respond differently to phosphorylation. BK channel open probability (Po) of all cells lines used was increased by H2S in ATP-containing solutions. PKA prevented the action of H2S on channel Po in GH4 and GH4 STREX, but not in GH3 cells. H2S, high significantly increased Po of all PKG pretreated cells. In the presence of PKC, which lowers channel activity, H2S increased channel Po of GH4 and GH4 STREX, but not those of GH3 cells. H2S increased open dwell times of GH3 cells in the absence of ATP significantly. A significant increase of dwell times with H2S was also observed in the presence of okadaic acid. CONCLUSIONS: Our results suggest that phosphorylation by PKG primes the channels for H2S activation and indicate that channel phosphorylation plays an important role in the response to H2S.

E. Dyukova, G. Sitdikova, R. Schreckenberg, Y. Abdallah, K.D. Schlüter Mechanisms by which calcium receptor stimulation modifies electromechanical coupling in isolated ventricular cardiomyocytes Pflügers Archiv - European Journal of Physiology February 2015, Volume 467, Issue 2, pp 379-388


     The calcium-sensing receptor (CaR) is widely expressed throughout the entire cardiovascular system and is capable of activating signaling pathways in different cells. Alongside calcium, the CaR also responds to physiological polycations such as putrescine underlining a participation in physiological and pathophysiological processes. Here, we aimed to determine mechanisms as to how CaR activation affects the contractile responsiveness of ventricular cardiomyocytes under basal and stimulated conditions. For that purpose, cardiac myocytes from 3-month-old male Wistar rats were isolated, and the acute effects of an antagonist (NPS2390), agonists (putrescine and gadolinium), or of downregulation of the CaR by siRNA on cell shortening were recorded in a cell-edge-detection system. In addition, experiments were performed on muscle stripes and Langendorff preparations. Mechanistic insights were taken from calcium transients of beating fura-2 AM-loaded cardiomyocytes and western blots. Isolated ventricular cardiomyocytes constitutively express CaR. The expression in the atria is less pronounced. Acute inhibition of CaR reduced basal cell shortening of ventricular myocytes at nearly physiological levels of extracellular calcium. Inhibition of CaR strongly reduced contractility of ventricular muscle stripes but not of atria. Activation of CaR by putrescine and gadolinium influences the contractile responsiveness of isolated cardiomyocytes. Increased calcium mobilization from the sarcoplasmic reticulum via an IP3-dependent mechanism was responsible for amplified systolic calcium transients and a subsequent improvement in cell shortening. Alongside with these effects, activation of CaR increased relaxation velocity of the cells. In conclusion, ventricular CaR expression affects contractile parameters of ventricular heart muscle cells and modifies electromechanical coupling of cardiomyocytes.

 M. Y. Shafigullin, R. A. Zefirov*, G. I. Sabirullina, A. L. Zefirov, and G. F. Sitdikova Effects of a Hydrogen Sulfi de Donor on Spontaneous Contractile Activity of Rat Stomach and Jejunum. Bulletin of Experimental Biology and Medicine, Vol. 157, No. 3, July, 2014 PHYSIOLOGY P302-306


      We studied the effect of sodium hydrosulfite (NaHS), a donor of hydrogen sulfide (H2S), on spontaneous contractive activity of isolated preparations of rat stomach and jejunum under isometric conditions. NaHS in concentrations of 10-200 μM reduced the amplitude, tonic tension, and frequency of contractions of the preparations. Blockade of K+ channels with a non-specific antagonist tetraethylammonium (10 mM) increased contraction amplitude in the stomach strip and jejunum segment. The effects of NaHS on all parameters of contractile activity of the stomach and jejunum were fully preserved against the background of tetraethylammonium application. These data suggest that H2S in physiologically relevant concentrations inhibited spontaneous contractile activity of smooth muscle cells in rat stomach and jejunum by reducing the amplitude and frequency of contractions and decreased tonic tension without affecting the function of voltage- and calcium-dependent K+ channels.

T. V. Baltina, M. V. Kuznetsov, A. A. Yeremeev, and M. E. Baltin. Effect of Vibratory Stimulation of Foot Support Areas in Rats on the Functional State of Leg Muscles and the Content of N2A Titin Isoforms in Gravity Relief // Biophysics.- 2014.- V. 59, No2. - P. 316–320. ISSN 00063509


      In this work, we studied the effect of vibratory stimulation of the foot support zones on the functional state of the leg muscles and the content of N2A titin isoforms in rats under simulated microgravity (suspension model). The results of this study showed that vibratory stimulation of the support zones of the rat foot in a gravity discharge may reduce the drop in the amplitude of leg muscle motor response and undesirable reduction of the titin content.

Guzel Sitdikova, Andrei Zakharov, Sona Janackova, Elena Gerasimova, Julia Lebedeva, Ana R. Inacio, Dilyara Zaynutdinova, Marat Minlebaev, Gregory L. Holmes, Roustem Khazipov;  Isoflurane suppresses early cortical activity  Annals of Clinical and Translational Neurology 2014; 1(1): 15–26 PDF


Objective Isoflurane and other volatile anesthetics are widely used in children to induce deep and reversible coma, but they may also exert neurotoxic actions. The effects of volatile anesthetics on the immature brain activity remain elusive, however.Methods The effects of isoflurane on spontaneous and sensory-evoked activity were explored using intracortical extracellular field potential and multiple unit recordings in the rat barrel cortex from birth to adulthood.Results During the first postnatal week, isoflurane suppressed cortical activity in a concentration-dependent manner. At surgical anesthesia levels (1.5–2%), isoflurane completely suppressed the electroencephalogram and silenced cortical neurons. Although sensory potentials evoked by the principal whisker deflection persisted, sensory-evoked early gamma and spindle-burst oscillations were completely suppressed by isoflurane. Isoflurane-induced burst-suppression pattern emerged during the second postnatal week and matured through the first postnatal month. Bursts in adolescent and adult rats were characterized by activation of entire cortical columns with a leading firing of infragranular neurons, and were triggered by principal and adjacent whiskers stimulation, and by auditory and visual stimuli, indicating an involvement of horizontal connections in their generation and horizontal spread.Interpretation The effects of isoflurane on cortical activity shift from total suppression of activity to burst-suppression pattern at the end of the first postnatal week. Developmental emergence of bursts likely involves a development of the intracortical short- and long-range connections. We hypothesize that complete suppression of cortical activity under isoflurane anesthesia during the first postnatal week may explain neuronal apoptosis stimulated by volatile anesthetics in the neonatal rats.

Cuellara, C.A. Spinal neurons bursting in phase with fictive scratching are not related to spontaneous cord dorsum potentials/ C.A. Cuellara, A. Trejo, P. Linares, R. Delgado-Lezama, I. Jiménez-Estrada, L.M. Abyazova, T.V. Baltina, E.Manjarrez. //Neuroscience.-V.266,No4 – 2014.- P.66–79


Spontaneous cord dorsum potentials (spontaneous CDPs) are produced by the activation of dorsal horn neurons distributed along the L4 to S1 spinal cord segments, in Rexed's laminae III-VI, in the same region in which there are interneurons rhythmically bursting during fictive scratching in cats. An interesting observation is that spontaneous CDPs are not rhythmically superimposed on the sinusoidal CDPs generated during fictive scratching episodes, thus suggesting that the interneurons producing both types of CDPs belong to different spinal circuits. In order to provide experimental data to support this hypothesis, we recorded unitary activity of neurons in the L6 spinal cord segment. We found that the neurons firing rhythmically during the sinusoidal CDPs associated with the extensor, flexor or intermediate phases of scratching were not synchronized with the spontaneous CDPs. Moreover, we found that the neurons firing during the spontaneous CDPs were not synchronized with the sinusoidal CDPs. These results suggest that the neurons involved in the occurrence of spontaneous CDPs are not part of the spinal cord central pattern generators (CPGs). This study will be relevant for understanding the relationships between the spinal cord neuronal populations firing spontaneously and the CPGs, in the intact and injured spinal cord.