Serotonin receptors types

When we talk about serotonin-blocking medications, a point of clarification must be made. In most cases, medications do not block overall serotonin activity but instead block the activity at one of the many serotonin receptor types. For example, the antidepressants trazodone, nefazodone, and mirtazapine increase total serotonin activity yet they block certain of the serotonin receptors. Mirtazapine increases both serotonin and norepinephrine activity by interfering with the alpha-2 receptor. By also blocking the serotonin-2 and serotonin-3 receptors, mirtazapine avoids the sexual dysfunction and GI side effects commonly experienced with other serotoninboosting medications. We cannot truly call these serotonin-blocking medications, because they are serotonin-boosting medications that selectively block certain serotonin receptors. 

There is only one type of receptor for each neurotransmitter. For example, there is only one serotonin receptor type. True or False. 

Kang H, Lee WK, Choi YH, et al. Molecular analysis of the interaction between the intracellular loops of the human serotonin receptor type 6 (5-HT6) and the alpha subunit of Gs protein. Biochem Biophys Res Commun 2005 329 684-692. 

The G-protein coupled receptors modulate intracellular cAMP level, which plays a crucial role in epidermal barrier homeostasis.5 Increase of intracellular cAMP in epidermal keratinocytes by topical application of forskolin delays barrier recovery, while cAMP antagonists accelerate the barrier recovery. Activation of dopamine 2-like receptors (manuscript in preparation), melatonin receptors, or serotonin receptor (type 5-HT1) decreases intracellular cAMP and consequently accelerates the barrier recovery (Figure 15.1), while activation of adrenergic 32 receptors increases intracellular cAMP and delays the barrier repair.6 Barrier disruption induces an increase of the intracellular cAMP level. Thus, topical application of agonists of receptors that reduce intracellular cAMP accelerates the barrier repair. Our results are summarized in Table. 15.1. 

BS has been shown to interact with dopamine receptors in vitro. Pharmacologically both DA agonists and antagonist properties have been demonstrated. There is also evidence that serotonin receptors (type 2) are involved as well as interaction with NE and ACh... 

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

Figure 2.13 BioPrint (partial) profile of compounds developed for activity against a serotonin receptor. Three compounds that attrited for some type of toxicity issue are shown at the bottom in a purple box. The serotonin receptors and transporters are highlighted with a blue box.

Martin P, Lemonnier F. (1994). [The role of type 2 serotonin receptors, 5-HT2A and 5-HT2C, in depressive disorders effect of medifoxamine]. Encephale. 20(4) 427-35. 

Over 95% of the body s serotonin (5-HT) is found in the gastrointestinal tract in enterochromaffin cells and neurons. There are 18 known serotonin receptor sub-types, of which 5-HT, 5-HT3, and 5-HT are located in the gut and modulate gut secretion, motility, and sensation (57). The 5-HT in the synaptic spaces stimulates these receptors until it is actively cleared by a 5-HT transporter protein located on the presynaptic neuronal endings. 

Psychiatric medicines exert multiple effects for two principal reasons. First, they usually interact with more than one receptor type. There are two ways to look at this. You will often hear a medication with multiple receptor interactions called a dirty drug. This is because the more receptor interactions it has, the more effects, and hence side effects, it produces. As a result, great effort has been made to develop newer medications with fewer receptor interactions and, thus, fewer side effects. This effort has been quite successful with antidepressants, as we have moved from the effective but side effect-laden tricyclic antidepressants to newer antidepressants such as selective serotonin reuptake inhibitors. 

There is another reason why medications exert multiple effects. For example, an antidepressant that very specifically promotes serotonin neurotransmission and has little or no interaction with other receptor types will still produce multiple effects. How can this be Remember that in different areas of the brain, a single neurotransmitter can assume very distinct roles. When an individual takes a medication that alters the activity of a particular neurotransmitter, it generally does so throughout the brain. Consequently, the dopamine receptor blocking effect of haloperidol (Haldol) reduces hallucinations and paranoia in one brain region but causes upper extremity stiffness through its action in another brain region. 

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

Several different types of serotonin receptor (for example, S-HTi / 5-HT2A/ 5-HT2C/ 5-HTib/id) have been associated with the motor side effects of the SSRIs which may arise should these drugs be administered in conjunction with a monoamine oxidase inhibitor. The 5-HT3 receptor is an example of a non-selective cation charmel receptor which is permeable to both sodium and potassium ions and, because both calcium and magnesium ions can modulate its activity, the 5-HT3 receptor resembles the glutamate-NMDA receptor. Antagonists of the 5-HT3 receptor, such as ondansetron, are effective antiemetics and are particularly useful when... 

HT3 antagonist serotonin receptor antagonist type 3... 

Serotonin mediates many central and peripheral physiological functions, including contraction of smooth muscle, vasoconstriction, food intake, sleep, pain perception, and memory, a consequence of it acting on several distinct receptor types. Although 5-HT may be metabolized by monoamine oxidase, platelets and neurons possess a high-affinity mechanism for reuptake of 5-HT. This mechanism may be inhibited by the widely prescribed antidepressant drugs termed selective serotonin re-uptake inhibitors (SSRl), e.g. fluoxetine (Prozac ), thereby increasing levels of 5-HT in the central nervous system. 

Ga-GDP has no affinity for the effector protein and reassociates with the p and Y subunits (A). G-proteins can undergo lateral diffusion in the membrane they are not assigned to individual receptor proteins. However, a relation exists between receptor types and G-protein types (B). Furthermore, the a-subunits of individual G-proteins are distinct in terms of their affinity for different effector proteins, as well as the kind of influence exerted on the effector protein. G -GTP of the Gs-protein stimulates adenylate cyclase, whereas G -GTP of the Gr protein is inhibitory. The G-protein-coupled receptor family includes muscarinic cholinoceptors, adrenoceptors for norepinephrine and epinephrine, receptors for dopamine, histamine, serotonin, glutamate, GABA, morphine, prostaglandins, leukotrienes, and many other mediators and hormones. 

Figure 7. A serotonergic synapse including a depiction of the acute tryptophan depletion method discussed in the text. All large neutral amino acids (SLNAAs) share a common blood-brain barrier transporter. The serotonergic precursor, tryptophan, essentially competes with the other LNAAs for transport. Thus tryptophan is uniquely susceptible to acute dietary manipulation. Numerous serotonergic receptor types exist, including presynaptic S-HTm and (somatodendritic) 5-HTia autoreceptors and postsynaptic 5-HTia, 5-HTid, 5-HT2a 5-HT2c 5-HT3 and 5-HT4 receptors. Additional modulation of serotonin activity can occur via the action of selective serotonin re-uptake inhibitors (SSRls) including fluoxetine, fluvoxamine, and citalopram.

Serotonin (5-hydroxytryptamine 5-HT) acts as transmitter and mediator on several locations in the body with quite different effects. There are multiple sub-types of the serotonin receptor. This offers the possibility of a selective therapeutic interference using subtype specific agonists or antagonists. 

Many different receptor types are coupled to G proteins, including receptors for norepinephrine and epinephrine (a- and p-adrenoceptors), 5-hydroxytrypta-mine (serotonin or 5-HT receptors), and muscarinic acetylcholine receptors. Figure 2.1 presents the structure of one of these, the uz-adrenoceptor from the human kidney. All members of this family of G protein-coupled receptors are characterized by having seven membrane-enclosed domains plus extracellular and intracellular loops. The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portions of the receptor. The general term for any chain of events initiated by receptor activation is signal transduction. 

The effect of the release of any neurotransmitter depends on the type of receptor that it binds. One challenge in understanding serotonergic function in the brain is that at least 18 subtypes of serotonin receptors have so far been found, each with its own mechanism of action. Scientists have debated the reasons for this extreme number of types of receptor for one neurotransmitter (serotonin outnumbers most other neurotransmitters in this regard). It has been suggested that this diversity allows for more complicated signaling between brain cells that could not occur with just one or two receptor types. As a result, communication between cells is not simply... 

The anxiolytic activity of several compounds in some, but not all, animal models of anxiety in fact suggests that different receptor subtypes may modulate different types of anxiety as discussed below. It would not be surprising if the specific serotonin links to disorders of anxiety also differ among the various disorders of anxiety such as generalized anxiety versus obsessive-compulsive disorder versus panic disorder versus social phobia versus mixed anxiety depression. Such studies are in progress, and much further research is necessary to clarify the potential links between subtypes of anxiety and subtypes of serotonin receptors. 

Cross AJ, Slater P, Perry EK, et al An autoradiographic analysis of serotonin receptors in human temporal cortex changes in Alzheimer-type dementia. Neurochem Int 13 89-96, 1988... 

There are two main families of ligand-gated ion channel proteins that act as ionotropic receptors. One family includes the nicotinic acetylcholine receptor, the GABA-A receptor, the glycine receptor, and a class of serotonin receptor. The other family comprises various types of ionotropic glutamate receptors. Since these various ligand gated ion channels are activated by neurotransmitters, the medicinal chemistry of these proteins is presented in detail in chapter 4. 

Four different receptor types have been the main focus of interest. These are muscarinic cholinergic, histamine HI, dopamine D2 (different from the vascular dopamine receptor), and serotonin 5-HT3. In addition, neurokinin NKl-receptor antagonists are undergoing early clinical trials. 

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