Receptor site characterization

Receptor models are powerful tools for source apportionment of particulates because a vast amount of particulate species characterization data have been collected at many sampling sites worldwide, and because many aerosol species are primary pollutants. Most of the information available is for elemental concentrations, eg, lead, nickel, and alurninum, although more recent measurements have provided data on concentrations of ionic species and carbonaceous compounds. At a sampling (or receptor) site, the aerosol mass concentration of each species i is... 

Zukin, S.R., and Zukin, R.S. Identification and characterization of 3H phencyclidine binding to specific brain receptor sites. In Domino, E.F., ed. PCP (phencvli di ne) Hi stori cal and... 

The acute CNS effects of MDMA administration are mediated by the release of monoamine transmitters, with the subsequent activation of presynaptic and postsynaptic receptor sites.40 As specific examples in rats, MDMA suppresses 5-HT cell firing, evokes neuroendocrine secretion, and stimulates locomotor activity. MDMA-induced suppression of 5-HT cell firing in the dorsal and median raphe involves activation of presynaptic 5-HT1A autoreceptors by endogenous 5-HT.4142 Neuroendocrine effects of MDMA include secretion of prolactin from the anterior pituitary and corticosterone from the adrenal glands 43 Evidence supports the notion that these MDMA-induced hormonal effects are mediated via postsynaptic 5-HT2 receptors in the hypothalamus, which are activated by released 5-HT. MDMA elicits a unique profile of locomotor effects characterized by forward locomotion and elements of the 5-HT behavioral syndrome such as flattened body posture, Straub tail, and forepaw treading.44 6 The complex motor effects of MDMA are dependent on monoamine release followed by activation of multiple postsynaptic 5-HT and DA receptor subtypes in the brain,47 but the precise role of specific receptor subtypes is still under investigation. 

The benzodiazepines bind to a specific GABA receptor site to affect mood, spasticity, seizures and sleep. The benzodiazepines are reported to be effective in certain chronic pain syndromes characterized by muscle spasm, concomitant chronic pain and anxiety. 

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. 

Finally, receptor modeling offers a useful theme around which to organize aerosol characterization studies. Large scale field studies are expensive, and they also tend to be diffuse. Data requirements for source resolution can be used to select the chemical and physical properties of the aerosol to be measured both at receptor sites and at sources. 

Tunicamycin specifically inhibits cell division and pairing between the mating types of Tetrahymena pyriformis. The glycoproteins involved in this mating process have not yet been characterized, but may coincide with new, concanavalin A receptor-sites that appear during conjugation.495... 

The results lead to the conclusion that a transport parameter such as log P or is a composite quantity and is a function of intermolecular forces. If this is the case, it follows that log P or may not always have a suitable composition for modeling a particular case of bioactivity. The dependence of bioactivity on Aimf should vary with the nature of the membrane to be crossed and with the nature of the receptor site to which the bioactive substance is to bind. The receptor site consists of some region on a biopolymer which is characterized by a gross shape and by some number of atoms and groups of atoms which constitute its surface. 

Once a receptor site is characterized structurally (and in the case of enzyme active sites, mechanistically), such information can be used for the de novo design of a lead compound (Section 3.3). 

Despite the problems that remain, it is clear that with the tremendous increase in number of receptor sites that are being characterized by X-ray, the computational approach to de novo ligand and eventually drug design will assume great importance in the years ahead. 

Intracellular recordings from taste cells of rat and hamster show that even primary receptor cells are sensitive tu three or four of the so-called basic taste modalities. Consequently, it is generally held that a variety or dilferem receptor sites commonly exist on the receptor membrane of anyone receptor cell. Biochemical characterization or events at receptor sites has progressed in analyzing electrolyte and carbuhydrate stimulation. 

Information may be stored in the architecture of the receptor, in its binding sites and in the ligand layer surrounding bound <7 it is read out at the rate of formation and dissociation of the supermolecule. In addition to size and shape, a receptor is characterized by the dimensionality, the connectivity and the cyclic order of its structural graph these features have been used to define a ligand structural index L ... 

The uptake of iron from transferrin into cells has been best studied for reticulocytes, where there is heavy demand for iron for the synthesis of heme. Reticulocytes and, by analogy, other mammalian cells have receptor molecules on their plasma surface which bind transferrin. Characterization of the transferrin receptor from rabbit reticulocytes suggests that it is probably a glycoprotein of molecular weight around 200 000. The number of receptor sites in cells varies in response to the conditions. For example, treatment of K562 cells with the efficient iron chelator desferrioxamine results in an increase in the total number of receptors for transferrin.1142... 

A principal interest in our laboratory is the molecular characterization of CNS receptor sites of the neurotransmitter dopamine (DA, 5). These sites are strongly implicated in the biochemical etiology of schizophrenia and Parkinson s Disease, as well as other diseases of the CNS (50,51). Thus, the rank order of clinical potency of antipsychotic drugs (neuroleptics) correlates with the affinity of these drugs for dopaminergic sites (52,53), It is also well established that Parkinson s disease is directly related to deterioration in dopaminergic neurotransmission in the corpus striatum, which is a brain region rich in dopamine receptor sites (54). The use of L-DOPA, the biosynthetic precursor of dopamine, in treatment of patients with Parkinson s disease is one of the best examples of biochemically directed medical treatment. 

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