The nicotinic receptors mediate synaptic transmission at the neuromuscular junction as described earlier; however, nicotinic receptors are also present within the CNS. The nicotinic receptor contains a relatively nonselective cationic channel, so binding of acetylcholine produces an EPSP. Being members of the cys-loop family, acetylcholine receptors are pentamers constructed from a series of subunit types called α, β, γ, δ, ε, some of which contain multiple members. At the neuromuscular junction the channel is constructed from 2α, β, δ, ε, whereas in the CNS the composition is typically 3α, 2β. Furthermore, the junctional receptors all use the α1 subunit, whereas centrally located receptors use one of the α subunits between α2 and α10. As noted, the differing subunits result in receptors with differing pharmacological sensitivities and channel kinetics and selectivity.
There are five known muscarinic subtypes of acetylcholine receptors (M1 to M5). All are metabotropic receptors; however, they are coupled to different G proteins and can thus have distinct effects on the cell. M1, M3, and M5 are coupled to pertussis toxin–insensitive G proteins, whereas M2 and M4 are coupled to pertussis toxin–sensitive G proteins. Each set of G proteins is coupled to different enzymes and second messenger pathways (see for details of these pathways).
Inhibitory Amino Acid Receptors: GABA and Glycine
As noted, the most common inhibitory synapses in the CNS use either glycine or GABA as their transmitter. Glycine-mediated inhibitory synapses are common in the spinal cord, whereas GABAergic synapses make up the majority of inhibitory synapses in the brain.
Both glycine and GABA have ionotropic receptors that are members of the cys-loop family, thus sharing a number of characteristics as already described. In addition, each of these receptors has a Cl− channel, which opens while the receptor portion is bound. Therefore, the probability of these channels opening and the average time a channel stays open are controlled by the concentration of the neurotransmitter for which the receptor is specific.
Glycine receptors are pentamers and may be heteromers of α and β subunits (3:2 ratio) or homomers. Interestingly, the molecular composition appears to be related to its cellular location, with heteromers located postsynaptically and homomers located extrasynaptically. The β subunit seems to bind to an intracellular scaffold protein called gephyrin that appears to help localize receptors to the postsynaptic site. The α subunit contains the glycine binding site, and there are four genes coding for distinct α subunits (and splice variants of each). Each variant results in a receptor having distinct conductance, kinetics, agonist and antagonist affinity, and modulatory sites. Intriguingly, subunit variants are differentially expressed during development and in different brain regions.