AMPA and kainate receptors function as classic ligand-gated channels. When glutamate binds to these receptors, the channel opens, allowing current to flow and generating an excitatory postsynaptic potential (EPSP). On the other hand, NMDA channels differ in their behavior. To open, they require both glutamate and glycine to bind. Additionally, these channels display voltage sensitivity due to the presence of Mg++ ions, which block the channel at resting or more negative membrane potentials. This means that even when glutamate and glycine are bound, no current can flow through the channel. However, depolarization of the cell can relieve the Mg++ block, enabling current to flow. Another interesting characteristic of NMDA channels is their permeability to Ca++, which can act as a second messenger. These voltage-sensitive and Ca++-permeable NMDA channels have led to hypotheses regarding their involvement in learning and memory-related functions.

Metabotropic glutamate receptors are classified into three groups and are encoded by eight genes. Group I receptors are located postsynaptically, while groups II and III are found presynaptically. These receptors generate slow EPSPs and, more importantly, trigger second messenger cascades.

Purines have two receptor families: ionotropic (P2X) and metabotropic (P2Y). The P2X family consists of seven identified subunit types that form channels. Each subunit has two transmembrane domains, and the extracellular loop between these domains contains the ATP binding site. These receptors can form heterotrimers, homotrimers, or hexamers. Typically, P2X receptors create a cationic channel that allows the permeability of Na+, K+, and Ca++. The distribution of subunits in the brain varies, with some having widespread distribution (such as P2X2) and others being more limited (such as P2X3, which is mainly present in cells involved in pain-related pathways).

Metabotropic purine receptors are coded by 10 genes, but only six are expressed in the human CNS. These receptors share typical characteristics of G protein-coupled receptors and are known to activate K+ currents and modulate both NMDA and voltage-gated Ca++ currents. Notably, P2Y receptors dominate on astrocytes, while both P2X and P2Y receptors are present on neurons.

In addition to P2X and P2Y receptors, there are also adenosine receptors that respond to adenosine released after the breakdown of ATP. These receptors are located presynaptically and inhibit synaptic transmission by blocking the influx of Ca++.

Biogenic amine receptors, including serotonin, dopamine, noradrenaline, adrenaline, and histamine receptors, primarily belong to the metabotropic-type receptors, except for the 5-HT3 class of serotonin receptors, which are ionotropic receptors belonging to the cys-loop family. As a result, these neurotransmitters act on relatively longer time scales by generating slow synaptic potentials and initiating second messenger cascades. Agonists and blockers targeting these receptors play crucial roles in the clinical treatment of various neurological and psychiatric disorders. The involvement of different dopamine receptors in basal ganglia disorders will be discussed in the motor systems section.
AMPA and kainate receptors behave as classic ligand-gated channels as already discussed; on binding of glutamate to the receptor, the channel opens and allows current to flow, thereby generating an EPSP. NMDA channels are different. First, they require binding of both glutamate and glycine to open. Second, they display voltage sensitivity as a result of Mg++ blockade of the channel. That is, at resting (or more negative) membrane potentials, a Mg++ ion blocks the entrance to the channel so that even when glutamate and glycine are bound, no current flows through the channel. However, if the cell is depolarized (either experimentally by injection of current through an electrode or by other EPSPs), the Mg++ block is relieved and current can flow through the channel. A further interesting feature of NMDA channels is that they are generally permeable to Ca++, which can act as a second messenger. The combination of voltage sensitivity and Ca++ permeability of the NMDA channels has led to hypotheses concerning their role in learning and memory-related functions (see
Eight genes coding for metabotropic glutamate receptors have been identified and classified into three groups. Group I receptors are found postsynaptically, whereas groups II and III are found presynaptically. These receptors generate slow EPSPs, but probably at least as importantly, they trigger second messenger cascades (see
Purines have two receptor families: an ionotropic (P2X) and a metabotropic (P2Y) family. There are seven identified P2X subunit types that form channels, and they represent their own superfamily of ligand-gated channels. Each subunit has only two transmembrane domains, with the loop between these two domains located extracellularly and containing the ATP binding site. The receptors are heterotrimers or homotrimers or hexamers. In general, these receptors form a cationic channel that is permeable to Na+ , K+ , and Ca++ . The distribution of subunits in the brain varies significantly, with some subunits having a widespread distribution (P2X2) and others being quite limited (P2X3 is present mostly on cells involved in pain-related pathways).
Metabotropic purine receptors are coded for by 10 genes, but only 6 are expressed in the human CNS. They have the typical features of G protein–coupled receptors and are known to activate K+ currents and modulate both NMDA and voltage-gated Ca++ currents. An interesting localization distinction between P2X and P2Y receptors is that although both are present on neurons, the latter dominates on astrocytes.
Finally, in addition to the P2X and P2Y receptors, which respond to ATP, there are adenosine receptors that respond to the adenosine that is released after the enzymatic breakdown of ATP. These receptors are located presynaptically and act to inhibit synaptic transmission by inhibiting influx of Ca++ .
Biogenic Amine Receptors: Serotonin, Dopamine, Noradrenaline, Adrenaline, Histamine
With the exception of one class of serotonin receptors (5-HT3) that are part of the cys-loop ionotropic family, receptors for the various biogenic amines are all metabotropic-type receptors. Thus, these neurotransmitters tend to act on relatively long time scales by generating slow synaptic potentials and by initiating second messenger cascades. Agonists and blockers of many of these receptors are important clinical tools for treating various neurological and psychiatric disorders. The role of different dopamine receptors in basal ganglia disorders will be covered in the motor systems (see