Laboratory is focused on the research of membrane receptors and secretion in neuroendocrine cells, with a special emphasis on the interactions between plasma membrane electrical events and receptor-controlled pathways. The Laboratory investigates signaling pathways at the cellular and molecular levels, determines the manner in which hormones and neurotransmitters utilize calcium and cyclic nucleotides as intracellular messengers, and characterizes channels involved in electrical activity, calcium signaling, and release of hormones and neurotransmitters.
Main topics:
- Purinergic signaling in neurons of suprachiasmatic and supraoptic nuclei of hypothalamus.
- Ligand-gated ion channels and electrical excitability of pituitary cells
- Relationship between structure and function of purinergic P2X receptor-channels
Projects
Conflicting reports exist regarding ATP modulation of synaptic transmission and electrical activity in vasopressin- and oxytocin-containing neurons from supraoptic nucleus (SON). We are using electrophysiological methods and calcium imaging on hypothalamic neurons of rat brain slices to study these properties.
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Purinergic P2X receptors (P2X1-7) are ligand-gated ion channels which binding sites for allosteric modulators are still not well understood. Activation of these receptors is the major signaling pathway of extracellular adenosine 5'-triphosphate (ATP) in neuroendocrine cells.
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Achievements
The ATP-gated P2X7 receptor channel operates as a cytolytic and apoptotic receptor but also controls sustained cellular responses, including cell growth, proliferation and secretion. Experimental data suggest that that aromatic residues in the upper part of the first transmembrane domain are critical for both the P2X7R channel pore opening and receptor sensitization, and residues located at or below the intersection of the second transmembrane domains control its conductivity.
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Allosteric modulators of ligand-gated receptor channels induce conformational changes of the entire protein that alter potencies and efficacies for orthosteric ligands, expressed as the half maximal effective concentration and maximum current amplitude, respectively. The influence of allostery on channel pore size, an issue not previously addressed, was studied.
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Ivermectin is a large lipophilic molecule that acts as a positive allosteric regulator of several ligand-gated channels including the glutamate-gated chloride channel, gamma aminobutyric acid type-A receptor, glycine receptor, neuronal alpha7-nicotinic receptor and purinergic P2X4 receptor. This review summarizes what is currently known about ivermectin binding and modulation of Cys-loop receptor family of ligand-gated ion channels and what are the critical structural determinants underlying potentiation of the P2X4 receptor channel.
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Corticotorpin releasing hormone (CRH), a key regulator of HPA axis, is secreted by hypothalamic paraventricular neurons into the hypophysial portal system and stimulates ACTH secretion in pituitary corticotorphs. The data show that resting membrane potential in corticotrophs depends on background voltage-insensitive sodium conductance, and that CRH has biphasic actions: a depolarizing effect driven by a cationic conductance at basal concentrations in pituitary portal circulation and an inhibitory effect at higher stress CRH concentrations
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Publications
Zemková, Hana - Stojilkovic, S. S.
Neurotransmitter receptors as signaling platforms in anterior pituitary cells
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Molecular and Cellular Endocrinology 2018, roč. 463, C, p. 49-64
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IF = 3.563
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doi
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Svobodová, Irena - Bhattacharya, Anirban - Ivetic, Milorad - Bendová, Z. - Zemková, Hana
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Circadian ATP Release in Organotypic Cultures of the Rat Suprachiasmatic Nucleus Is Dependent on P2X7 and P2Y Receptors
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Frontiers in Pharmacology 2018, roč. 9, Mar 6, článku 192
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IF = 3.831
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doi
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Stojilkovic, S. S. - Bjelobaba, I. - Zemková, Hana
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Ion Channels of Pituitary Gonadotrophs and Their Roles in Signaling and Secretion
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Frontiers in Endocrinology. 2017, roč. 8, Jun 9, článku 126
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IF = 3.519
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doi
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Mackay, L. - Zemková, Hana - Stojilkovic, S. S. - Sherman, A. - Khadra, A.
Deciphering the regulation of P2X4 receptor channel gating by ivermectin using Markov models
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PLoS Computational Biology. 2017, roč. 13, 7, článku e1005643
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IF = 3.955
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doi
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Fletcher, P. A. - Zemková, Hana - Stojilkovic, S. S. - Sherman, A.
Modeling the diversity of spontaneous and agonist-induced electrical activity in anterior pituitary corticotrophs
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Journal of Neurophysiology. 2017, roč. 117, 6, p. 2298-2311
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IF = 2.502
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Zemková, Hana - Tomič, M. - Kučka, M. - Aguilera, G. - Stojilkovic, S. S.
Spontaneous and CRH-Induced Excitability and Calcium Signaling in Mice Corticotrophs Involves Sodium, Calcium, and Cation-Conducting Channels
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Endocrinology. 2016, roč. 157, 4, p. 1576-1589
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IF = 4.286
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doi
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Zemková, Hana - Khadra, A. - Rokic, Milos Boro - Tvrdoňová, Vendula - Sherman, A. - Stojilkovic, S. S.
Allosteric regulation of the P2X4 receptor channel pore dilation
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Pflugers Archiv - European Journal of Physiology. 2015, Vol. 467, 4, p. 713-726
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IF = 3.654
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doi
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Jindřichová, Marie - Bhattacharya, Anirban - Rupert, Marian - Skopek, Petr - Obšil, T. - Zemková, Hana
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Functional characterization of mutants in the transmembrane domains of the rat P2X7 receptor that regulate pore conductivity and agonist sensitivity
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Journal of Neurochemistry. 2015, Vol. 133, 6, p. 815-827
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IF = 3.842
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doi
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Zemková, Hana - Tvrdoňová, Vendula - Bhattacharya, Anirban - Jindřichová, Marie
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Allosteric modulation of ligand gated ion channels by ivermectin
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Physiological Research 2014, roč. 63, suppl.1, s215-s224. ISSN 0862-8408.
IF = 1.293
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Tvrdoňová, Vendula - Rokic, Milos Boro - Stojilkovic, S. S. - Zemková, Hana
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Identification of Functionally Important Residues of the Rat P2X4 Receptor by Alanine Scanning Mutagenesis of the Dorsal Fin and Left Flipper Domains
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PLoS ONE 2014, roč. 9, 11, e112902. ISSN 1932-6203.
IF = 3.234
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Show more
Cellular localization of P2X2 receptors in supraoptic nuclei of hypothalamus Immunohistochemistry on the rat hypothalamic slices containing supraoptic nucleus and optic chiasm (OC). P2X2R immunoreactivity (green) is observed in somata of the supraoptic neurons. Staining was performed using antibodies against the P2X2R (green), neuronal marker NeuN (red) and glia cell marker GFAP (blue). Scale is 50 µm.
