Gated Ion Channels Ionotropic Receptors

Key Words Serotonin3 receptor 5-hydroxytryptamine3 receptor Cys-loop receptor ligand-gated ion channel ionotropic receptor neurotransmitter binding site. 

For differentiation of G-protein-coupled receptor sub-types from subtypes permanently linked to ion channels (ligand-gated ion channels) the terms metabotropic versus ionotropic receptors, respectively, are used. Prime examples of metabotropic receptors are given by the lnGlu receptor family of G-protein-coupled glutamate receptors. 

P2 receptors are subdivided into ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptors are ionotropic ligand-gated ion channels (P2Xi 7). There are... 

Ionotropic receptors (bottom left) are ligand-gated ion channels. When they open as a result of the transmitter s influence, ions flow in due to the membrane potential (see p. 126). If the inflowing ions are cations (Na"", C, Ca ""), depolarization of the membrane occurs and an action potential is triggered on the surface of the postsynaptic cell. This is the way in which stimulatory transmitters work (e.g., acetylcholine and glutamate). By contrast, if anions flow in (mainly Cl ), the result is hyperpolarization of the postsynaptic membrane, which makes the production of a postsynaptic action potential more dif cult. The action of inhibitory transmitters such as glycine and GABA is based on this effect. 

Ionotropic receptors are ligand-gated ion channels (left half of the table). The receptors for stimulatory transmitters (indicated in the table by a ) mediate the inflow of cations (mainly Na""). When these open after binding of the transmitter, local depolarization of the postsynaptic membrane occurs. By contrast, inhibitory neurotransmitters (GABA and glycine) allow cr to flow in. This increases the membrane s negative resting potential and hinders the action of stimulatory transmitters hyperpolarization, 0). 

There are two main families of ligand-gated ion channel proteins that act as ionotropic receptors. One family includes the nicotinic acetylcholine receptor, the GABA-A receptor, the glycine receptor, and a class of serotonin receptor. The other family comprises various types of ionotropic glutamate receptors. Since these various ligand gated ion channels are activated by neurotransmitters, the medicinal chemistry of these proteins is presented in detail in chapter 4. 

The amino acid L-glutamate is the main excitatory neurotransmitter of the central nervous system (Fonnum, 1984). Glutamate exerts its excitatory effects either by activation of several G-protein-coupled metabotropic glutamate receptors or by induction of ion fluxes by different classes of ionotropic receptors. The NMDA receptor is one of those glutamate-gated ion channels which got its name from its selective artificial agonist NMDA (N-methyl-D-aspartate) and which controls slow but persistent ion fluxes of Na+, K+, and Ca2+ across the cell membrane. 

Fig. 1 Structures of subunits (top) and subunit oligomerization (bottom) in ligand-gated ion channels. (a) P2X receptor family, (b) Ionotropic glutamate receptor family, (c) TRPV channel family, (d) Cys-loop superfamily comprising nAChRs, 5-HT3,GABAa, and glycine receptors.

When comparing transmitter-gated ion channels on a functional level, one can discern between anion and cation channels. The former ones comprise the GABAa and glycine receptors, which display a rank order of anion selectivity of I- > Hr > Cl- and which are also permeable to HC()3. All other ionotropic receptors mentioned here are cation channels, which discriminate rather poorly between various monovalent cations, at least when compared with voltage-gated ion channels. Some... 

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