Neurotransmitters, Receptors And Their Pathways
Neurotransmitters and synaptic function
The neurotransmitter released at a synapse interacts with a specific protein in the postsynaptic membrane, known as a receptor. At some synapses the neurotransmitter also binds to a presynaptic autoreceptor that regulates the amount of transmitter that is released.
Receptors are usually specific for a given neurotransmitter, although several different types of that receptor may exist. In some cases co-released neurotransmitters can either modulate the binding of another neurotransmitter to its receptor or act synergistically on a common single ion channel (e.g. the γ-aminobutyric acid [GABA]–benzodiazepine–barbiturate receptor).
Receptors for specific neurotransmitters are either coupled directly to ion channels (T1R on figure, e.g. acetylcholine receptors (AChR); see Chapter 16) or to a membrane enzyme (T2R). In these latter instances the binding of the neurotransmitter to the receptor either opens an ion channel via an intracellular enzyme cascade (e.g. cyclic adenosine monophosphate [cAMP] and G-proteins) or indirectly modulates the probability of other ion channels opening in response to voltage changes (neuromodulation). These receptors therefore mediate slower synaptic events, unlike those receptors directly coupled to ion channels that relay fast synaptic information.
The activated receptor can only return to its resting state once the neurotransmitter has been removed either by a process of enzymatic hydrolysis or uptake into the presynaptic nerve terminal or neighbouring glial cells. Even then there are often intermediate steps in the process of returning the receptor and its associated ion channel to the resting state. At some synapses the affinity and, ultimately, the number of receptors is dependent on the previous activity of the synapse. For example, at catecholaminergic synapses the receptors become less sensitive to the released transmitter when the synapse is very active – a process of desensitization and down-regulation. This process involves a decrease in the affinity of the receptor for the transmitter in the short term, which goes on in the long term to an actual decrease in the number of receptors. The converse is true with synapses that are rarely activated (super-sensitivity and up-regulation), and in this way synaptic activity is modulated by its ongoing activity.
In addition, at some synapses the activation of the postsynaptic receptor–ion channel complex can modulate the long-term activity of the synapse, either by affecting the presynaptic release of neurotransmitter or the postsynaptic receptor response – a process known as either long-term potentiation (LTP) or long-term depression (LTD) depending on the actual change in synaptic efficacy over time (see Chapters 45 and 49). Therefore the state, number and types of receptor for a specific neurotransmitter as well as the presence of receptors to other neurotransmitters are all important in determining the extent of synaptic activity at any given synapse.
Diversity and anatomy of neurotransmitter pathways
The nervous system employs a large number of neurotransmitters, which can be divided into groups (see also Chapter 19).
Excitatory amino acids
These represent the main excitatory neurotransmitters in the central nervous system (CNS) and are important at most synapses in maintaining ongoing synaptic activity. The main excitatory amino acid is glutamate, which acts at a number of receptors (which are defined by the agonists that activate them). The inotropic receptors consist of the N-methyl-D-aspartate (NMDA) and non-NMDA receptors, and the former receptor with its associated calcium channel may be important in the generation of LTP (see Chapter 45), excitotoxic cell death (see Chapter 60) and possibly epilepsy (see Chapter 61).
A separate group of G-protein associated glutamate receptors, the metabotropic receptors, respond on activation by initiating a number of intracellular biochemical events that modulate synaptic transmission and neuronal activity. These receptors may underlie long-term depression in the hippocampus.
Inhibitory amino acids
The major CNS inhibitory neurotransmitters are GABA, which is present throughout the CNS, and glycine which is predominantly found in the spinal cord. Abnormalities of GABA neurones may underlie some forms of movement disorders as well as anxiety states and epilepsy (see Chapters 59 and 61). While mutations in the glycine receptor have now been linked to some forms of hyperexplexia – a condition in which there is an excessive startle response, such that any stimulus induces a stiffening of the body with collapse to the ground without any impairment of consciousness.
The monoaminergic systems of the CNS originate from small groups of neurones in the brainstem, which then project widely to all areas of the CNS. They are found at many other sites within the body, including the autonomic nervous system (ANS; see Chapter 3). In all locations they bind to a host of different receptors and thus can have complex actions including a role in depression, schizophrenia, cognition and movement control (see Chapters 41, 42, 47, 57 and 58).
This neurotransmitter is widely distributed throughout the nervous system, including the neuromuscular junction (see Chapter 16) and ANS (see Chapter 3). Therefore, many agents have been developed that target the different cholinergic synapses in the periphery and which are used routinely in surgical anaesthesia. Several disease processes can affect the peripherally located cholinergic synapses (see Chapter 16), while secondary abnormalities in the central cholinergic pathways may be important in dementia of the Alzheimer type and Parkinson’s disease (see Chapters 42 and 60).
These neurotransmitters, of which there are many different types, are found in all areas of the nervous system and are often co- released with other neurotransmitters. They can act as conventional neurotransmitters as well as having a role in neuromodulation (e.g. pain pathways; see Chapters 32 and 38).