Get to know serotonin receptors

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. The 5-HT1, 2, 4, 5, 6 and 7 receptors belong to the G-protein coupled superfamily. They are membrane receptors that have 7 transmembrane spanning a-helices. 5-HT 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 is either inhibitory or stimulatory, depending on the type of G-protein linked to the receptor – 5-HT1 receptors are linked to inhibitory G-proteins, whereas 5-HT2, 4, 6 and 7 are linked to stimulatory G-proteins.

www.cnsforum.com

References

Histamine, serotonin and the ergot alkaloids. In: Basic and clinical pharmacology, 8^th edition. Katzung BG. USA: The McGraw Hill Companies, Inc, 2001:265–291

How drugs act: molecular aspects. In: Pharmacology, 4^th edition. Rang HP, Dale MM and Ritter JM. Edinburgh, UK: Harcourt Publishers Ltd, 2001:19–46.

The 5-HT3 receptor is distinct from the other 5-HT receptor subtypes, in that it is a ligand-gated ion channel that is permeable to sodium and potassium. The 5-HT3 receptor is structurally similar to the nicotinic acetylcholine receptor and is composed of 5 subunits. Two subunits have been cloned, 5-HT3A and 5-HT3B, and homomeric (5-HT3A) and heteromeric (5-HT3A/5-HT3B) forms of the receptor have both been characterised

Binding of an agonist at the 5-HT binding site causes a conformational change and activation of the 5-HT3 receptor. As a ligand gated ion channel this permits the movement of positively charged ions from the synaptic cleft into the cytoplasm. Binding of an antagonist at the 5-HT binding site prevents this activation and cell depolarisation is inhibited.

A 5-HT1A receptor antagonist prevents the activation of the 5-HT1A receptor. The 5-HT1A receptor is coupled to inhibitory G-proteins, which dissociate from the receptor on agonist binding, and inhibit secondary messenger signaling mechanisms. Antagonist binding inhibits this usual process, resulting in cell depolarisation.

Binding of a partial agonist to the 5-HT1A receptor causes the dissociation of inhibitory G-proteins. The G-protein alpha sub-unit binds to and inhibits adenylate cyclase. This prevents the conversion of ATP to cAMP and the initiation of other secondary messenger signaling mechanisms, hence cell depolarisation is inhibited.

A 5-HT2 receptor antagonist prevents the activation of the 5-HT2 receptor. The 5-HT2 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.

G-protein coupled receptors

Before I explain serotonin receptors family I want to go over in deep detail about G-protein coupled receptors, and we will examine closely about specific serotonin subtypes and their functions., This will give us insight of how atypical antipsychotics work and clues of how these agents cause side effects. I have a nice illustration and description to show you below.

Robert T. Dorsam and J. Silvio Gutkind, G-protein-coupled receptors and cancer, Nature Reviews Cancer 7, 79-94 (February 2007)

Various ligands use G-protein-coupled receptors (GPCRs) to stimulate membrane, cytoplasmic and nuclear targets. GPCRs interact with heterotrimeric G proteins composed of , and subunits that are GDP bound in the resting state. Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of GDP from the subunit followed by GTP-binding to G and the dissociation of G from G subunits.

The subunits of G proteins are divided into four subfamilies: G_s, G_i, G_q and G₁₂, and a single GPCR can couple to either one or more families of G proteins. Each G protein activates several downstream effectors. Typically G_s stimulates adenylyl cyclase and increases levels of cyclic AMP (cAMP), whereas G_i inhibits adenylyl cyclase and lowers cAMP levels, and members of the G_q family bind to and activate phospholipase C (PLC), which cleaves phosphatidylinositol bisphosphate (PIP₂) into diacylglycerol and inositol triphosphate (IP₃).

The G subunits and G subunits function as a dimer to activate many signalling molecules, including phospholipases, ion channels and lipid kinases.

Besides the regulation of these classical second-messenger generating systems, G subunits and G subunits such as G₁₂ and G_q can also control the activity of key intracellular signal-transducing molecules, including small GTP-binding proteins of the Ras and Rho families and members of the mitogen-activated protein kinase (MAPK) family of serine-threonine kinases, including extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38 and ERK5, through an intricate network of signalling events that has yet to be fully elucidated. Ultimately, the integration of the functional activity of the G-protein-regulated signalling networks control many cellular functions, and the aberrant activity of G proteins and their downstream target molecules can contribute to cancer progression and metastasis.

5-HT, 5-hydroxytryptamine; ECM, extracellular matrix; GABA, gamma-aminobutyric acid; GEF, guanine nucleotide exchange factor; GRK, G protein receptor kinase; LPA, lysophosphatidic acid; PI3K, phophatidylinositol 3-kninase; PKA and PKC, protein kinase A and C; S1P sphingosine-1-phosphate.

Dopamine theory – that’s all for schizophrenia?

Scientists know that pathology in the mesolimbic and mesocortical pathways causes schizophrenia, or simply called psychosis. Are there any other neurotransmitters causing the disease? I will start with the hypothesis that “Dopamine involves with schizophrenia.” Scientists found evidences that support this hypothesis, and it becomes the most fully developed more than several hypotheses. If I were about to test the hypothesis, first, I would think that if I introduce a drug that will enhance DA releasing in the brain to schizophrenics and non-schizophrenics, at a certain level of the drug, I would be able to see aggravation of the symptoms in schizophrenics group and I would expect to see schizophrenia-like symptoms in non-schizophrenics group. Second, if I use DA blocking agents in schizophrenics their symptoms would be alleviated. Third, I am going to do positron emission tomography (PET) to see the difference in DA receptors density in schizophrenics and non-schizophrenics. Actually, scientists have done these experiments and they confirm that DA involves in schizophrenia. They have also investigated postmortem brains and found the increase in DA receptors density in schizophrenics who have not been treated with antipsychotic drugs. Another evidence that support DA theory is changing in the level of homovanillic acid (HVA), a metabolite of DA, in the cerebrospinal fluid, plasma, and urine in the patients who were successfully treated. These experiments confirm that DA involves in schizophrenia, but can we make a conclusion that DA system is the system and the only system that plays an important role in schizophrenia? In greater detail are there any subtypes of DA receptors that play different roles? These questions arose because antipyschotic drugs did not give therapeutic results as good as they were expected. For examples, in a group of patients who have had the psychosis for ten to thirty years, a PET (Positron Emission Topography) scan revealed 90% of D2 receptor binding of antipsychotic drugs but the patients had minimal reduction in psychoses. However, the PET scan in a group of first-episode patients showed 60-70% D2 receptor binding, but the patients responded to low dose antipsychotics. In addition, it is found that typical antipsychotics selectively bind to D2 receptor 50 times more than binding to D1 and D3 receptors. These data support a hypothesis that selective D2 blocking has no significant in increasing antipsychotic activity, and therefore the research trend, in stead of focusing only on improving selectivity and potency of blocking D2 receptor, has been changed to a broader consideration–new drugs with less D2 selectivity.

Below is a nice illustration and explanation of DA receptor subtypes borrowed from www.cnsforum.com. I am going to discuss about this slide and other pathways that involve schizophrenia on Monday. Have a nice weekend.

“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.”

Fight Schizophrenia!

People with schizophrenia need support from their families and people around them. There is no absolute cure for the disease, but there are ways to help them overcoming the symptoms and preventing a recurrence of the symptoms. When talking about schizophrenia, I think about these: first, the pathology of dopamine pathways. Second, the first agents–reserpine and chlopromazine that was found to alleviate the symptoms since 1950’s, and they are called typical antipsychotic drugs. Third, atypical antipsychotic drugs which are newer agents that have less side effects than the typical one. Fourth, the side effects of antipsychotic medications. Fifth, the drug interactions with this type of medication. And the lastly, sixth, how long people with schizophrenia should take the medications.

Many books use slightly different terminology for dopamine (DA) pathways; however, they base on the same concept in which the pathways are named after the area of the brain that neurons that release DA innervate. Here is the illustration borrowed from the Genetic Science Learning Center of the University of Utah.

[LEFT] The first–nigrostriatal pathway–extends from the substantia nigra to the caudate nucleus-putamen (neostriatum) and is concerned with sensory stimuli and movement. The death of neurons in this pathway can result in Parkinson’s disease.

[MIDDLE] The second–mesolimbic and mesocortical pathway–projects from the ventral tegmentum to the mesolimbic forebrain and is thought to be associated with memory, motivation, emotional response, reward, desire, and addiction. Pathology in this area causes schizophrenia.

[RIGHT] The third pathway, known as the tubero-infundibular system, extends from hypothalamus to pituitary gland, and is responsible for hormone regulation, maternal behavior (nurturing), pregnancy and sensory processes.

Now we know that the pathology in the mesolimbic and mesocortical pathway causes schizophrenia. Tomorrow I am going to write about DA theory in the mesolimbic and mesocortical pathway and how typical and atypical antipsychotic drugs act on this pathway.