Neurotransmitter interactions with receptors

The actions of neurotransmitters are mediated mostly through their interactions with receptors located either at presynaptic or postsynaptic sites. These receptors function in a coordinated fashion to elicit excitation (depolarization) or inhibition (hyperpolarization) within and between neuronal subsystems. A basic inadequacy in this interplay is believed to lead to pathologic states... 

Figure 18.3. Endocrine-immune inter-relationship in depression. In depression, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback controls. Corticotrophin releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocortico-trophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

There is a great deal of evidence that deficiency of serotonin (5-hydroxytryptamine) is a factor in depressive illness, and many antidepressant drugs act to decrease its catabolism or enhance its interaction with receptors. A key enzyme involved in the synthesis of serotonin (and the catecholamines) is aromatic amino acid decarboxylase, which is pyridoxal phosphate-dependent. Therefore, it has been suggested that vitamin Be deficiency may result in reduced formation of the neurotransmitters and thus be a factor in the etiology of depression. Conversely, it has been suggested that supplements of vitamin Be may increase aromatic amino acid decarboxylase activity, and increase amine synthesis and have a mood-elevating or antidepressant effect. There is little evidence that vitamin Be deficiency affects the activity of aromatic amino acid decarboxylase. In patients with kidney failure, undergoing renal dialysis, the brain concentration of pyridoxal phosphate falls to about 50% of normal, with no effect on serotonin, catecholamines, or their metabolites (Perry etal., 1985). 

Both the older tricyclic antidepressants and the more recent drugs related to fluoxetine owe their efficacy to interaction with receptors for the neurotransmitters epinephrine, serotonin, and dopamine. The... 

Cyclizations of organolithiums onto pyrrole or aromatic rings leading to a fused heterocycle activation of the cyclizations by oxazolinyl substitutents use of dearomatization cyclization in the synthesis of cainoids, pyrrolidine-2,3-dicarboxylic acid derivatives capable of interaction with receptors of neurotransmitters 04S1721. 

In order to answer that, we have to move down once more to the molecular level and understand what happens when a small molecule such as a drug or a neurotransmitter interacts with a receptor protein. 

Regulated by neurotransmitter interactions with specific receptors. Such receptors may be directly linked to ion channels or change ion channel function via second-messenger effector systems. 

Receptors are either an integral protein in the cell membrane (type 1, 2 and 3 below) or a protein in the cytoplasm or the nucleus (type 4). They form the site where the chemical messengers of the body, hormones and neurotransmitters, interact with cells. Many drugs... 

The events that take place at a synapse, that is synthesis of neurotransmitter, storage in vesicles, release, interaction with receptors and eventual inactivation provide targets for drug action (Chapter 3). Inactivation of a neurotransmitter can be by re-uptake into the neuron it was released from (as with noradrenaline and dopamine), or by the action of enzymes in the synaptic cleft (as with acetylcholine). 

Released neurotransmitter interacts with postsynaptic receptors (E) and, in the case of G protein-coupled receptors, activates second messenger systems (F). The action of 5-HT is terminated (G) either by diffusion of 5-HT away from the synapse, with subsequent metabolism, or by the 5-HT being taken back up by a 5-HT transporter into the presynaptic neuron (i.e., reuptake), where it can be stored or metabolized. 

When a nerve impulse arrives at a synapse, it causes the release of a minute amount of a chemical substance called a neurotransmitter (or synaptic transmitter) which is a localized hormone. This substance diffuses across the gap and, on reaching the far side, it interacts with receptors (on the postsynaptic membrane of a muscle or nerve cell. As soon as it has acted, the neurotransmitter is removed from the synaptic cleft, either by reabsorption into the presynaptic store (norepinephrine) or by enzymic destruction (acetylcholine). In this way, the synapse is rapidly restored to its resting state and is then ready to respond to another impulse. 

The poison dart frogs of Central and South America store toxic substances such as the acetylenic alkaloid histrionicotoxin within their bodies to deter attacks by other animals. Histrionicotoxin disrupts neuromuscular transmission in animals through its interaction with receptors for the neurotransmitter acetylcholine. 

Three important neurotransmitters are derived from aromatic L-amino adds by decarboxylation followed by hydroxylation. Likewise, the ergoline ring system is derived from L-tryptophan, which has been decorated (prenylated and iV-methyl-ated), and decarboxylated in the process. The implication of this similarity in origins is that structures of noradrenaline, dopamine and 5-hydroxytryptamine (serotonin) can be mapped almost entirely onto the ergoline ring structure. This, it is believed, is why many clavine and EA can interact with receptors for all three of these neurotransmitters (102). 

Within the DA neuron, DA is synthesized from its precursor, tyrosine, and packaged into vesicles, small spherical cellular structures utihzed for neurotransmitter storage. The arrival of an action potential leads to a process termed exocy-tosis [2]. For this process, Ca + influx causes the fusion of the DA-containing vesicles with the cell membrane within the synapse, the space between consecutive neurons. A fusion pore forms initially and then opens further to release the contents of the vesicle into the extracellular fluid. DA can then diffuse aaoss the synapse (1-100 mn) and interact with receptors on the membrane of either... 

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