What predisposes people to mental illness? Written for a genetics class under the tutelage of Steve Jones in December 2008, this paper comprises a review of animal and human studies of the genetics of serotonin and its reuptake transporter and their implications on our understanding of mental illness and was originally titled ‘5-HT: serotonin, the reuptake transporter, its genetics, and serotonergic disease’.
Serotonin’s role in nature is manifold: it is found in both plants and animals, and in the animal kingdom it acts as a neurotransmitter in a range of species as well as having a role in the human gastrointestinal tract, the cardiovascular system and in bone and glucose metabolism (Jonnakuty & Gragnoli, 2008). This paper outlines the role of serotonin in humans, particularly its role as a neurotransmitter, and explores the genetics of the serotonin reuptake transporter, animal and human studies into the genetic polymorphisms therein and their effect on mental illnesses in humans.
Neurotransmitters and the role of serotonin
Since its discovery in the late 1940s, serotonin has been the subject of considerable research and of more than 15,000 papers in the last twenty years alone. The general level of interest in serotonin is likely to do with its apparent ubiquity in human physiology: its effects are wide-ranging, and it plays a part in determining levels of aggression, in appetite, in sexual activity, in diseases such as cardiovascular disorders and migraines, and in a range of mental illnesses including depression, anxiety and schizophrenia (Aghajanian & Sanders-Bush, 2001).
Serotonin’s most prominent and most extensively researched role in human physiology is as a neurotransmitter—a chemical which relays electrical signals between neurons (that is, across synapses). Each neurotransmitter has a different role in the brain: acetylcholine is involved with involuntary movement, REM sleep and learning; dopamine is implicated in anticipatory pleasure and reward-seeking behaviour, and so on.
The mechanism of operation of neurotransmitters is essentially quite simple, comprising transmission, binding and reuptake: upon stimulation by an action potential, the neurotransmitter is released from the presynaptic neuron into the gap between two neurons (the synaptic cleft) from where it binds to specific receptors on the postsynaptic axon, transmitting the action potential to the next neuron. Reuptake transporter proteins on the presynaptic neuron then pass the neurotransmitter back into the presynaptic axon for re-use.
Mammals express a variety of specialised serotonin receptors, each of which has its own effects when stimulated. Serotonin’s ability to control multiple receptors and signalling pathways is only just beginning to be understood and the importance of this appreciated. Serotonin also seems to have an important role to play in homeostasis: research using knockout mice shows the importance of specific serotonin receptors in glucose metabolism in particular (Drago, Ronchi, & Serretti, 2008).
Serotonin’s role specifically as a neurotransmitter involves the mediation of motor control, circadian rhythm, appetite, metabolism, REM sleep and mood, the latter of which has been the subject of great interest over the last twenty years. Drugs which block the reuptake of serotonin, so increasing the level of free serotonin in the synaptic cleft (so-called selective serotonin reuptake inhibitors or SSRIs) are now the most widely-prescribed type of antidepressant, yet their exact mode of action is still not properly understood. Suffice it to say that while serotonin’s importance in the worlds of genetics, pharmacology and medicine has been well and truly cemented, it is far from being fully understood.
Serotonin has its own specialised postsynaptic receptors presently numbering more than fifteen (Glennon et al., 2000). Confusing the issue is that fact that human and animal serotonin receptors differ somewhat, with several named receptors being mouse homologues of human serotonin receptors. Serotonin itself binds to all the receptors and an assortment of other drugs and chemicals variously bind to the different receptors.
A variety of common serotonin receptor polymorphisms have been implicated in mental illness (Serretti et al., 2007a, b). Not only do these polymorphisms affect the lifetime probability of an individual suffering from mental illness, but they also influence individuals’ responses to psychiatric drugs. The field of pharmacogenetics aims to bring together genetic and molecular models of drug action to allow responses to drugs to be better understood, and ultimately to tailor drugs, drug regimens and gene therapies to a patient’s exact genotype.
Pages: 1 2 3 4
Serotonin, disease and the future
What predisposes people to mental illness? Written for a genetics class under the tutelage of Steve Jones in December 2008, this paper comprises a review of animal and human studies of the genetics of serotonin and its reuptake transporter and their implications on our understanding of mental illness and was originally titled ‘5-HT: serotonin, the reuptake transporter, its genetics, and serotonergic disease’.
Serotonin’s role in nature is manifold: it is found in both plants and animals, and in the animal kingdom it acts as a neurotransmitter in a range of species as well as having a role in the human gastrointestinal tract, the cardiovascular system and in bone and glucose metabolism (Jonnakuty & Gragnoli, 2008). This paper outlines the role of serotonin in humans, particularly its role as a neurotransmitter, and explores the genetics of the serotonin reuptake transporter, animal and human studies into the genetic polymorphisms therein and their effect on mental illnesses in humans.
Neurotransmitters and the role of serotonin
Since its discovery in the late 1940s, serotonin has been the subject of considerable research and of more than 15,000 papers in the last twenty years alone. The general level of interest in serotonin is likely to do with its apparent ubiquity in human physiology: its effects are wide-ranging, and it plays a part in determining levels of aggression, in appetite, in sexual activity, in diseases such as cardiovascular disorders and migraines, and in a range of mental illnesses including depression, anxiety and schizophrenia (Aghajanian & Sanders-Bush, 2001).
Serotonin’s most prominent and most extensively researched role in human physiology is as a neurotransmitter—a chemical which relays electrical signals between neurons (that is, across synapses). Each neurotransmitter has a different role in the brain: acetylcholine is involved with involuntary movement, REM sleep and learning; dopamine is implicated in anticipatory pleasure and reward-seeking behaviour, and so on.
The mechanism of operation of neurotransmitters is essentially quite simple, comprising transmission, binding and reuptake: upon stimulation by an action potential, the neurotransmitter is released from the presynaptic neuron into the gap between two neurons (the synaptic cleft) from where it binds to specific receptors on the postsynaptic axon, transmitting the action potential to the next neuron. Reuptake transporter proteins on the presynaptic neuron then pass the neurotransmitter back into the presynaptic axon for re-use.
Mammals express a variety of specialised serotonin receptors, each of which has its own effects when stimulated. Serotonin’s ability to control multiple receptors and signalling pathways is only just beginning to be understood and the importance of this appreciated. Serotonin also seems to have an important role to play in homeostasis: research using knockout mice shows the importance of specific serotonin receptors in glucose metabolism in particular (Drago, Ronchi, & Serretti, 2008).
Serotonin’s role specifically as a neurotransmitter involves the mediation of motor control, circadian rhythm, appetite, metabolism, REM sleep and mood, the latter of which has been the subject of great interest over the last twenty years. Drugs which block the reuptake of serotonin, so increasing the level of free serotonin in the synaptic cleft (so-called selective serotonin reuptake inhibitors or SSRIs) are now the most widely-prescribed type of antidepressant, yet their exact mode of action is still not properly understood. Suffice it to say that while serotonin’s importance in the worlds of genetics, pharmacology and medicine has been well and truly cemented, it is far from being fully understood.
Serotonin has its own specialised postsynaptic receptors presently numbering more than fifteen (Glennon et al., 2000). Confusing the issue is that fact that human and animal serotonin receptors differ somewhat, with several named receptors being mouse homologues of human serotonin receptors. Serotonin itself binds to all the receptors and an assortment of other drugs and chemicals variously bind to the different receptors.
A variety of common serotonin receptor polymorphisms have been implicated in mental illness (Serretti et al., 2007a, b). Not only do these polymorphisms affect the lifetime probability of an individual suffering from mental illness, but they also influence individuals’ responses to psychiatric drugs. The field of pharmacogenetics aims to bring together genetic and molecular models of drug action to allow responses to drugs to be better understood, and ultimately to tailor drugs, drug regimens and gene therapies to a patient’s exact genotype.
Pages: 1 2 3 4