Receptors and Human Nervous System Disorders

Abstract

Neurons, building blocks of the mammalian nervous system, mainly communicate with each other through synapses in which signal transmission is mediated by neurotransmitters released from the presynaptic neuron and sensed by the postsynaptic neuron. These endogenous chemicals released from the nerve terminal diffuse through the very narrow extracellular space between the neurons and bind to specific membrane proteins called receptors, thereby mediating signal propagation. Receptors are divided into two large families comprising those causing the activation of second messengers and those including an ionic pore which opens upon neurotransmitter binding and which controls flow of ions across the cell membrane. Also called ligandā€gated ion channels (LGIC), they mediate fast neurotransmission essential for the complex signal processing in the central nervous system. Reliable transmission of signals between neurons is highly dependent on accurate functioning of LGICs. Genetically transmissible nervous system disorders can be caused by mutations in genes coding for LGICs, resulting in dramatically altered neurotransmission.

Key Concepts

  • In this work we review the determinant role of ligand gated ion channels in brain function and the alterations related to genetic variants.

Keywords: synaptic transmission; neurotransmitter; receptors; brain; neurological disorders

Figure 1. Events at a chemical synapse. (a) The action potential (represented in the right panel) propagates along the axon and reaches the synaptic bouton (presynaptic ending). Voltage‐dependent calcium channels are represented on the bouton (closed state). (b) Depolarisation caused by the action potential provokes the opening of the calcium channels and a rapid increase in intracellular calcium that triggers the release of the neurotransmitter contained in the vesicles. (c) Neurotransmitter diffuses in the synaptic cleft and binds to receptors where it triggers the postsynaptic events.
Figure 2. Three‐dimensional structure of the principal ligand‐gated ion channels and hydropathy profiles and two‐dimensional structure of the ligand‐gated channels. (A) Schematic representation of the purinergic receptors with their two transmembrane domains. Both and terminals are intracellular. (B) Representation of the glutamate receptor family with three transmembrane domains. A short amino acid segment comprised between M1 and M3, the hair‐pin loop which is supposed to border the ionic pore is schematised. (C) Topology of the four transmembrane domain receptors. Glycosylation sites in the extracellular and phosphorylation sites in the intracellular domain are symbolised. Positions of the ligand‐binding site are represented by the grey boxes. Right panels illustrate in a cartoon manner the structural components of the three families of receptors. The grey areas indicate the segment of the protein that contributes to the formation of the ligand‐binding site.
Figure 3. Structure of the nicotinic acetylcholine receptor. (a) Ribbon diagram of the nicotinic acetylcholine receptor protein crystal structure. (b) Schematic representation of the nAChR in the cell membrane and cross section showing the neuronal subunits and binding sites for acetylcholine.
Figure 4. Presynaptic receptors modulate the release of neurotransmitter. The schematic diagram presented in the upper part illustrates the effects of ligand‐gated ion channels expressed in the presynaptic bouton. Activation of these receptors causes an increase in the intracellular calcium concentration and subsequently the release of neurotransmitter. Activation of presynaptic receptors is evidenced by an increase in the synaptic activity as shown by the recording presented in the lower panel.
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Further Reading

http://www.ncbi.nlm.nih.gov/disease/

http://www.hapmap.org/

http://clinicalstudies.info.nih.gov/cgi/protinstitute.cgi?NIMH.0.html

http://exac.broadinstitute.org

https://gene.sfari.org/GeneDetail/GLRA2

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Knoflach, Frédéric, and Bertrand, Daniel(Jan 2017) Receptors and Human Nervous System Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005164.pub3]