Receptor sub-types

Cotecchia S et al (2004) Structural determinants involved in the activation and regulation of G protein-coupled receptors lessons from the ai -adrenergic receptor sub-types. Biol Cell 96 327-333... 

For differentiation of G-protein-coupled receptor sub-types from subtypes permanently linked to ion channels (ligand-gated ion channels) the terms metabotropic versus ionotropic receptors, respectively, are used. Prime examples of metabotropic receptors are given by the lnGlu receptor family of G-protein-coupled glutamate receptors. 

The neuropeptide Y (NPY) belongs to a family of peptides that includes peptide YY and pancreatic polypeptide, and it is associated with several diseases such as asthma, immune system disorders, inflammatory diseases, anxiety, depression and diabetes mellitus. NPY is found in the central and peripheral nervous system, and its biological functions are mediated by interactions with five receptor sub-types, i.e. Yl, Y2, Y4, Y5 and Y6. Several studies indicate that the feeding behavior is influenced by interactions between NPY and Yl and Y5. Deswal and Roy used Cerius descriptors and genetic function approximation QSAR to investigate the structural determinants for the inhibition potency of 24 compounds with the general structure 4 for the NPY Y5 receptor [31]. The best QSAR (H = 0.720,... 

Two 5-HT receptor sub-types, 5-HT3 and 5-HT4, are involved in gut motility, visceral sensitivity, and gut secretion. The 5-HT3 receptors slow colonic transit and increase fluid absorption, whereas 5-HT4 receptor stimulation results in accelerated colonic transit. 

Perhaps the largest gap in the evidence surrounds the primary site of action of nicotine in the brain - the acetylcholine receptor itself. Studies on links with tobacco dependence in humans will await closer definition of the complex interaction between nicotine and its receptor and the identification of the receptor sub-types that are important in addiction pathways (see Section 22.4). 

Kong H, Raynor K, Yasuda K, Bell GI, Reisine T. Mutation of an aspartate at residue 89 in somatostatin receptor sub-type 2 prevents Na regulation of agonist binding but does not alter receptor/G protein association. Mol Pharmacol 1993 44 380-384. 

Rudolph, U., Crestani, F., Benke, D., Brunig, I., Benson, J. A., Fritschy, J. M., et al. (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor sub-types. Nature 401, 796-800. 

Brickley, S. G., Cull-Candy, S. G., and Farrant, M. (1999) Single-channel properties of synaptic and extrasynaptic GABAA receptors suggest differential targeting of receptor sub-types. J. Neurosci. 19,2960-2973. 

Sieghart, W. (1995) Structure and pharmacology of y-aminobutyric acidA receptor sub-types. Pharmacol. Rev. 47,181-234. 

Despite the discovery of ERcx selective SERMs and their subsequent use as chemical tools to evaluate the pharmacological significance of this receptor sub-type, the respective roles that ERcx and ER(3 play in regulating tissue selectivity is not yet clear. As a result, the identification of non-receptor subtype selective SERMs remains of considerable interest. Along these lines, isochroman 26 and... 

Hagan RM, Hughes IE. (1984). Opioid receptor sub-types involved in the control of transmitter release in cortex of the brain of the rat. Neuropharmacology. 23(5) 491-95. 

Ishizuka, T., Murata, N., Kanda, T., Kobayashi, I., Ohta, H., Ui, M. and Okajima, F., 1999, Comparison of intrinsic activities of the putative sphingosine 1-phosphate receptor sub-types to regulate several signaling pathways in their cDNA-transfected Chinese hamster ovary cells. J. Biol. Chem. 274 23940-23947. 

It is now widely accepted that there are at least three opioid receptor sub-types, mu kappa and delta. During the last decade increasing evidence has accumulated to support the hypothesis that a selective kappa opioid agonist will be a powerful analgesic without the clinically limiting side-effects that characterise morphine (e.g., respiratory depression, constipation, addiction)... 

These differences in the behavioural properties of the opioid receptor sub-types are of considerable interest because the clinical use of currently marketed opioid analgesic drugs is limited by their undesirable side-effects, which include respiratory depression, constipation and an abuse or dependence liability. These side-effects have been associated with mu receptor ac-... 

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. 

From the point of view of drug discovery, ligands acting at the G-protein-coupled receptors have resulted in most successful drug candidates.Some of the examples illustrating how receptor research has led to more selective drugs and enhanced our understanding of the roles played by various receptor sub-types in disease processes are mentioned below. Early examples of different receptor subtypes... 

Studies in mice with a targeted inactivation of other 5-HT receptor sub-types, such as the S-HTsa and 5-HT7, or a transgenic line that overexpresses 5-HT3, demonstrate that these receptors modulate the activity of neural circuits involved specifically in exploratory and reward-related behavior. When exposed to novel environments, KO mice lacking the S-HTsa exhibit increased exploratory activity and an attenuated stimulatory effect of lysergic acid diethylamide (LSD) on exploratory activity but no change in anxiety-related behavior (Grailhe et al. 1999), whereas S-HTy KO mice do not express any overt behavioral phenotype at all (Hedlund et al. 2003). 

Molecular genetic techniques have confirmed the existence of multiple subtypes of p-adrenoceptors. Pi-Receptors and Pj-receptors have been cloned, and recent molecular biological evidence indicates the existence of at least one additional p-receptor sub-type, called the p3-receptor. It is suggested that the P3-receptor may mediate some of the metabolic effects of catecholamines, although no available p-blocker has been shown to rely on Pa-receptor antagonism for its therapeutic effectiveness. 

More recently, we have been addressing a problem described previously concerning the relationship between morphine and enkephalin. The inherent mobility of the enkephalin framework, its rapid degradation in vivo/1341 and the existence of multiple receptor sub-types 135 136] have hampered the assessment of its bioactive conformations. Conformationally... 

Table 3.2 Sequence identities (%) between adenosine receptor sub-types from different species (data are taken from the GPCRDB All against all pairwise identity matrix (http //www.gpcr.org/7tm old/ seq/OO 1/OO1. PCTID.html))...

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