Synaptic Neurotransmitter-Gated Receptors

Abstract

Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families.T o understand how neurons communicate with each other requires a fundamental understanding of neurotransmitter receptor structure and function. Neurotransmitter-gated ion channels, also known as ionotropic receptors, are responsible for fast synaptic transmission. They decode chemical signals into electrical responses, thereby transmitting information from one neuron to another. Their suitability for this important task relies on their ability to respond very rapidly to the transient release of neurotransmitter to affect cell excitability.In the central nervous system (CNS), fast synaptic transmission results in two main effects: neuronal excitation and inhibition. For excitation, the principal neurotransmitter involved is glutamate, which interacts with ionotropic (integral ion channel) and metabotropic (secondmessenger signaling) receptors. The ionotropic glutamate receptors are permeable to cations, which directly cause excitation. Acetylcholine and serotonin can also activate specific cationselective ionotropic receptors to affect neuronal excitation. For controlling cell excitability, inhibition is important, and this is mediated by the neurotransmitters GABA and glycine, causing an increased flux of anions. GABA predominates as the major inhibitory transmitter throughout

Allosteric and hyperekplexic mutant phenotypes investigated on an α 1 glycine receptor transmembrane structure

“…For instance, we showed that performing the F119Y and M121F mutations on Lily results in an acceleration of the desensitization kinetics (16). Extensive mutagenesis work has shown that the entire interface is involved in fine tuning of the allosteric response to agonist (18,19).…”

Calcium Signaling in Dendritic Spines

“…Structurally, NMDARs are heteromeric tetramers typically consisting of two obligatory GluN1 subunits and two accessory GluN2 subunits (see Smart and Paoletti 2012). Some subunits also have multiple isoforms and, in some cases, multiple splice variants Sugihara et al 1992).…”

The Postsynaptic Organization of Synapses

“…Among the better understood groups are the membrane proteins, which include the cardinal functional proteins of the excitatory synapsethe glutamate receptors (AMPA, NMDA, and metabotropic glutamate receptors)-as well as other ion channels and adhesion molecules (see Smart and Paoletti 2011;Missler et al 2011).…”