PROSITE documentation PDOC00209

Neurotransmitter-gated ion-channels signature

Neurotransmitter-gated ion-channels [1,2,3,4] provide the molecular basis for rapid signal transmission at chemical synapses. They are post-synaptic oligomeric transmembrane complexes that transiently form a ionic channel upon the binding of a specific neurotransmitter. Presently, the sequence of subunits from five types of neurotransmitter-gated receptors are known:

• The nicotinic acetylcholine receptor (AchR), an excitatory cation channel. In the motor endplates of vertebrates, it is composed of four different subunits (α, β, γ and delta or epsilon) with a molar stoichiometry of 2:1:1:1. In neurones, the AchR receptor is composed of two different types of subunits: α and non-α (also called β). Nicotinic AchRs are also found in invertebrates.
• The glycine receptor, an inhibitory chloride ion channel. The glycine receptor is a pentamer composed of two different subunits (α and β).
• The γ-aminobutyric-acid (GABA) receptor, which is also an inhibitory chloride ion channel. The quaternary structure of the GABA receptor is complex; at least four classes of subunits are known to exist (α, β, γ, and delta) and there are many variants in each class (for example: six variants of the α class have already been sequenced).
• The serotonin 5HT3 receptor. Serotonin is a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen. There are seven major groups of serotonin receptors; six of these groups (5HT1, 5HT2, and 5HT4 to 5HT7) transduce extracellular signal by activating G proteins, while 5HT3 is a ligand-gated cation-specific ion channel which, when activated causes fast, depolarizing responses in neurons.
• The glutamate receptor, an excitatory cation channel. Glutamate is the main excitatory neurotransmitter in the brain. At least three different types of glutamate receptors have been described and are named according to their selective agonists (kainate, N-methyl-D-aspartate (NMDA) and quisqualate).

All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence.

The sequence of subunits from the AchR, GABA, 5HT3, and Gly receptors are clearly evolutionary related and share many regions of sequence similarities. These sequence similarities are either absent or very weak in the Glu receptors.

In the N-terminal extracellular domain of AchR/GABA/5HT3/Gly receptors, there are two conserved cysteine residues, which, in AchR, have been shown to form a disulfide bond essential to the tertiary structure of the receptor. A number of amino acids between the two disulfide-bonded cysteines are also conserved. We have therefore used this region as a signature pattern for this subclass of proteins.