Classification of Neurotransmitter Receptors
There are two broad classes of neurotransmitter receptors: those that contain an integral ion channel that is gated by ligand binding and those that are G protein-coupled (Table 1). The ligand-gated channels are also known as ionotropic receptors and the G protein-coupled receptors are known as metabotropic receptors.
Table 1 Classification of Neurotransmitter Receptors
| A. Ligand-Gated Ion Channels |
|---|
| multiple subunits, either three, four or five subunits for complete receptor |
| integral ion channel, gated by ligand binding |
| ≈ 80 genes in mammalian genome encode ligand-gated ion channel subunits |
| underlie fast synaptic transmission |
| B. G Protein-Coupled Receptors |
|---|
| receptor is generally a single polypeptide with seven membrane spanning domains |
| ligand binding activates G-proteins, which are intermediary effector proteins |
| ≈ 750 genes in genome encode G protein-coupled receptors |
| underlie slow synaptic transmission and neuromodulation |
Classic examples of ligand-gated ion channels are the nicotinic acetylcholine receptor and the glutamate receptor (Table 2). Classic examples of G protein-coupled receptors include the adrenergic receptors and the muscarinic acetylcholine receptors (Table 3). Many neurotransmitters, including acetylcholine, GABA, glutamate, serotonin, and ATP, have receptors of both types.
Table 2 Common Ligand-Gated Ion Channels
| Neurotransmitter | Receptor |
|---|---|
| Acetylcholine | nicotinic acetylcholine receptor |
| GABA | GABAA receptor |
| Glycine | glycine receptor |
| Glutamate | glutamate receptor |
| Serotonin | 5-HT3 receptor |
| ATP | purinergic receptors |
Table 3 Common G Protein-Coupled Receptors
| Neurotransmitter | Receptor |
|---|---|
| Acetylcholine | muscarinic acetylcholine receptor |
| GABA | GABAB receptor |
| Glutamate | metabotropic glutamate receptor |
| Norepinephrine (noradrenaline) | adrenergic receptor |
| Serotonin | 5-HT1 receptor |
| ATP | purinergic receptors |
| Dopamine | dopamine receptor |
| Neuropeptides | includes: opioid, substance P, NPY and VIP receptors |
There is no homology between these two different families of receptors. This is true even for receptors that bind the same neurotransmitter, such as the nicotinic and muscarinic acetylcholine receptors.
The G protein-coupled receptors belong to a single very large gene family, containing hundreds of members. The large size of this gene family reflects both the large number of different neurotransmitters that act through receptors of this type as well as the role of G protein-coupled receptors in many different non-neuronal signaling pathways.
The mechanism of action of these two types of receptors is fundamentally different (Figure 1). For the ligand-gated ion channels, the ion channel forms an integral part of the receptor. For the G protein-coupled receptors the linkage to the effector protein (channel or enzyme) is more convoluted, involving at least one intermediary protein, the G-protein. Not surprisingly then, the ligand-gated channels are much faster acting, they can open within microseconds of agonist binding whereas the G protein-coupled receptors generally act more slowly, typically acting in the hundred millisecond to second time frame.
Figure 1 Comparison of ligand-gated ion channels and G protein-coupled receptors.
Receptors within the same family can have quite different physiological effects. The ligand-gated ion channels can be either excitatory or inhibitory. The excitatory channels (acetylcholine, glutamate) are cation selective. The inhibitory channels (GABA, glycine) are anion selective. The G protein-coupled receptors can have a myriad of different actions, dependent upon which effector proteins they activate.
Ligand-Gated Ion Channels
Within the ligand-gated ion channel family there are three distinct gene families (Table 4). The three main families of ligand-gated channels are the Cys-loop receptors, the glutamate receptors and the purinergic (P2X) receptors (Table 4). These three families share no homology or evolutionary history.
Table 4 Ligand-Gated Ion Channels
| A. Cys-loop Receptors |
|---|
| pentamers |
| monovalent cation (some have Ca2+ permeability) or anion channels |
| neurotransmitters: acetylcholine, GABA, glycine, serotonin |
| B. Glutamate Receptors |
|---|
| tetramers |
| monovalent cation channels (some have Ca2+ permeability) |
| neurotransmitter: glutamate, three subtypes: AMPA, NMDA, Kainate |
| C. Purinergic (P2X) Receptors |
|---|
| trimers |
| cation channels |
| neurotransmitter: ATP |