ABSTRACT
Glycine receptor is the anion-selective channel, providing fast synaptic transmission in the central nervous system of vertebrates. Together with the nicotinic acetylcholine, GABA and serotonin (5-HT3R) receptors, it belongs to the superfamily of pentameric cys-loop receptors. It has been cloned one beta and four alpha subunits of glycine receptor, which are specifically distributed in different areas of the nervous system. Due to their specific molecular properties and distribution, different subunits ensure important physiological functions: from control of motor activity and regulation of neuronal differentiation to sensory information processing and modulation of pain sensitivity. In this review we briefly describe main functions of these transmembrane proteins, their distribution and molecular architecture. Special attention is paid to recent studies on the molecular physiology of these receptors, as well as on presenting of molecular domains responsible for their modulation and dysfunction.
Subject(s)
Central Nervous System/physiology , Motor Activity/physiology , Neurons/metabolism , Protein Subunits/metabolism , Receptors, Glycine/metabolism , Animals , Cell Differentiation , Central Nervous System/ultrastructure , Humans , Neurons/ultrastructure , Organ Specificity , Protein Multimerization , Protein Structure, Secondary , Protein Structure, Tertiary , Protein Subunits/chemistry , Protein Subunits/genetics , Receptors, Glycine/chemistry , Receptors, Glycine/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolismSubject(s)
Neurophysiology/history , History, 20th Century , History, 21st Century , Humans , Portraits as Topic , RussiaSubject(s)
Synapses , Cytoskeleton/metabolism , Cytoskeleton/physiology , Cytoskeleton/ultrastructure , Dendritic Spines/metabolism , Dendritic Spines/physiology , Dendritic Spines/ultrastructure , Humans , Nerve Net , Neuronal Plasticity/physiology , Post-Synaptic Density/metabolism , Post-Synaptic Density/physiology , Post-Synaptic Density/ultrastructure , Protein Transport , Synapses/metabolism , Synapses/physiology , Synapses/ultrastructure , Synaptic Transmission/physiologyABSTRACT
Synapses are highly organized, specific structures assuring rapid and highly selective interactions between cells. Synaptic transmission involves the release of neurotransmitter from presynaptic neurons and its detection by specific ligand-gated ion channels at the surface membrane of postsynaptic neurons. The protenomic analysis shows that for self-formation and functioning of synapses nearly 2000 proteins are involved in mammalian brain. The core complex in excitatory synapses includes glutamate receptors, potassium channels, CaMKII, scaffolding protein and actin. These proteins exist as part of a highly organized protein complex known as the postsynaptic density (PSD). The coordinated functioning of the different PSD components determines the strength of signalling between the pre- and postsynaptic neurons. Synaptic plasticity is regulated by changes in the amount of receptors on the postsynaptic membrane, changes in the shape and size of dendritic spines, posttranslational modification of PSD components, modulation kinetics of synthesis and degradation of proteins. Integration of these processes leads to long-lasting changes in synaptic function and neuronal networks underlying learning-related plasticity, memory and information treatment in nervous system of multicellular organisms.
Subject(s)
Dendrites/metabolism , Nerve Tissue Proteins/metabolism , Neuronal Plasticity/physiology , Neurotransmitter Agents/metabolism , Synaptic Membranes/metabolism , Synaptic Transmission/physiology , Animals , Humans , ProteomicsABSTRACT
Glycine receptors (GlyRs) provide the main inhibitory neurotransmission in spinal cord and brainstem synapses of vertebrates. Fucile et al. (2000) discovered that elevation of intracellular Ca2+ caused rapid potentiation of GlyRs. This modulation develops in less than 100 ms. It is characterized by an increase in GlyR apparent affinity for glycine. It has been suggested that the phenomenon of Ca-induced potentiation involves an unknown Ca2+-binding protein (CaBP). Using the yeast two-hybrid system, screening of human brain cDNA library against the cytoplasmic loop of human alpha 1 subunit (GlyRhl) allowed us to identify five new interactors. One of them belongs to a family of Ca-binding proteins. We analyzed effect of "short" forms of this protein (CaBP-S) on functional properties of GlyRhl expressed in HEK-293 and CHO cells. Using whole-cell recordings and rapid agonist application we constructed concentration dependencies of glycine-induced currents. This analysis revealed statistical differences in EC50s between control cells (expressing only GlyRhl) and those expressing CaBP-S. In HEK-293 cells recorded under conditions of low intracellular Ca concentration (BAPTA 20 mM in the recording pipette), EC50 for glycine in control cells and expressing GlyRhl + CaBP-S were, correspondently, 68+/-49 microM (n = 29) and 409 +/-421 microM (n = 60). In CHO cells EC50 were 54+/-43 microM (n = 25) and 123 +/-104 microM (n = 28). These differences were statistically not significant at recording with intracellular solution containing high Ca concentration (50 microM). In this case EC50 were correspondently 35+/-28 microM (n = 7) and 64 +/-38 microM (n = 7). These results suggest that CaBP-S causes decrease of GlyR sensitivity to agonist through interaction with cytoplasmic domain of GlyR.
Subject(s)
Calcium-Binding Proteins/metabolism , Receptors, Glycine/metabolism , Animals , CHO Cells , Calcium Channels , Cell Line, Tumor , Cricetinae , Cricetulus , Cytoplasm/metabolism , Electric Conductivity , Humans , Protein BindingSubject(s)
Ion Channels/physiology , Muscle, Smooth, Vascular/physiology , Aorta/physiology , Humans , In Vitro Techniques , Male , Membrane Potentials , Methods , Middle AgedABSTRACT
The molecular structure of acetylcholine receptors (AChR) of Lymnaea stagnalis neurons has been studied using specific agents to definite chemical groups. The disulphide bond important for AChR function was discovered, the reduction of which by dithiotreitol (DTT) inactivates AChR. The drugs exciting AChR protect the disulphide bond against modification with DTT likely due to the conformational changes of an active site and its environment. Desensitized AChR can also be modified by DDT (if it is not occupied by agonist). It is suggested that the system transmitting the conformational change from the AChR active site to its ionophore is responsible for desensitization.
Subject(s)
Acetylcholine/pharmacology , Ganglia/physiology , Lymnaea/physiology , Receptors, Cholinergic , Animals , Binding Sites , Chemical Phenomena , Chemistry , Dithiothreitol , Parasympatholytics , Protein Conformation , Receptors, Cholinergic/drug effects , Receptors, Cholinergic/metabolismABSTRACT
The influence of pH on acetylcholine (ACh)-induced responses in completely isolated neurons of Lymnaea stagnalis was studied under voltage clapm conditions. The pH drop lead to a decrease in sensitivity of cholinoreceptive membrane; at pH 5.8-6.0 ACh-responses were eliminated completely. When raising the external pH (up to 10.6) there were no changes in the ACh effect. A group responsible for sensitivity changes of the cholinoreceptive membrane appears to have pK about 6.7. It is shown that the pH drop does not influence the ionic channel functional groups. The results can be explained in the assumption that some functionally important groups in the cholinoreceptor active site are protonated at low pH.
