There are five sub-types of dopamine receptor and subtypes D1–D5 are widely distributed throughout both the cerebral cortex and the limbic system. Certain sub-types are also found in other specific areas of the brain, for example the D1 and D2 receptors are expressed in the corpus striatum.
There are four broad ‘superfamilies’ of receptor: (1) the channel-linked (ionotropic) receptors; (2) the G-protein coupled (metabotropic) receptors; (3) the kinase-linked receptors; and (4) receptors that regulate gene transcription. Dopamine receptors belong to the G-protein coupled superfamily. They are membrane receptors that have 7 transmembrane spanning a-helices. Dopamine binding to the ‘binding groove’ on the extracellular portion of the receptor activates the G-proteins, which initiate secondary messenger signalling pathways. The downstream effect will be either inhibitory or stimulatory, depending on the types of G-protein linked to the receptor – dopamine D1, D5 receptors are linked to inhibitory G-proteins, whereas dopamine D2, D3, D4 are linked to stimulatory G-proteins.
A D1 receptor antagonist prevents the activation of the dopamine D1 receptor. The D1 receptor is coupled to stimulatory G-proteins, which dissociate from the receptor on agonist binding and initiate secondary messenger signaling mechanisms. This causes cell depolarisation, which is inhibited by antagonist binding.
A D2 receptor antagonist prevents the activation of the dopamine D2 receptor. The D2 receptor is coupled to inhibitory G-proteins, which dissociate from the receptor on agonist binding and inhibit secondary messenger signaling mechanisms. This causes inhibition of down-stream signaling mechanisms. Antagonist binding inhibits this usual process, resulting in cell depolarisation.
There are two main subgroups of dopamine receptor — D1-like and D2-like. The D1-like receptor family contains the D1 and D5 receptor subtypes and the D2-like family contains the D3 and D4 subtypes. The D1-like receptors are found throughout the brain and in blood vessels and smooth muscle. Dopamine D1-like receptors are coupled to stimulatory G-proteins and they have a stimulatory effect on neurotransmission when bound by an agonist. Regions of the brain with a high density of D1-like receptors tend have a low density of D2-like receptors whereas regions of the brain with a low D1-like receptor density have a high density of D2-like receptors.
There are two main subgroups of dopamine receptor – D1-like and D2-like. The D2-like family contains the D2, D3 and D4 subtypes and the D1-like receptor family contains the D1 and D5 receptor subtypes. The D2-like receptors are found throughout the brain and in smooth muscle and presynaptic nerve terminals. Coupled to inhibitory G-proteins, dopamine D2-like receptors have an inhibitory effect on neurotransmission when bound by an agonist. Many neuroleptic drugs are antagonists of the D2 receptors. This class of drug is used to treat psychotic disorders, such as schizophrenia.
There are two types of dopamine receptor, D1-like and D2-like receptors. The D1-like receptors comprise D1- and D5-receptor subtypes that are associated with stimulation of adenylate cyclase. The D2-like receptors comprise D2-, D3- and D4-receptor subtypes and these are associated with inhibition of adenylate cyclase. The known functions of dopamine appear to be mediated mainly by D2-like receptors. All dopamine receptor subtypes are expressed in the brain in distinct but overlapping areas. D1 receptors are the most abundant and widespread in areas receiving dopaminergic innervation (the striatum, limbic system, thalamus and hypothalamus); D2 receptors are widespread in these areas, as well as the pituitary gland. D3 and D4 receptors are present in the limbic system. Schizophrenia is associated with dopaminergic hyperactivity. Dopamine antagonists used as antipsychotic drugs (eg chlorpromazine, haloperidol, risperidone) exert their effects mainly by blocking D2-like receptors. Dopamine agonists, such as apomorphine and bromocriptine, also have greater potency at D2-like receptors. Bromocriptine is used clinically to suppress prolactin secretion arising from tumours of the pituitary gland.
The action of dopamine at the synapse is terminated by its re-uptake across the pre-synaptic membrane. This is an energy dependent process. Sodium/potassium ATPases use energy from ATP hydrolysis to create a concentration gradient of ions across the pre-synaptic membrane that drives the opening of the transporter and co-transport of sodium and chloride ions and dopamine from the synaptic cleft. Potassium ions binding to the transporter enable it to return to the outward position. Release of the potassium ions into the synaptic cleft equilibrates the ionic gradient across the pre-synaptic membrane. The dopamine re-uptake transporter is then available to bind another dopamine molecule for re-uptake.