Receptor types

Receptors are macromolecules that bind mediator substances and transduce this binding into an effect, i.e., a change in cell function. Receptors differ in terms of their structure and the manner in which they translate occupancy by a ligand into a cellular response (signal transduction). 

There are various G-proteins that differ mainly with regard to their a-unit Association with the receptor activates the G-protein, leading in turn to activation of another protein (enzyme, ion channel). A large number of mediator substances act via G-protein-coupled receptors (see p. 66 for more details). 

An example of a ligand-gated ion channel (B) is the nicotinic cholinocep-tor of the motor endplate. The receptor complex consists of five subunits, each of which contains four transmembrane domains. Simultaneous binding of two acetylcholine (ACh) molecules to the two a-subunits results in opening of the ion channel, with entry of Na+ (and exit of some 1 +), membrane depolarization, and triggering of an action potential (p. 

The ganglionic N-cholinoceptors apparently consist only of a and p subunits (a2P2). Some of the receptors for the transmitter y-aminobutyric acid (GABA) belong to this receptor family  

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The insulin receptor protein represents a ligand-operated enzyme (C), a catalytic receptor. When insulin binds to the extracellular attachment site, a tyrosine kinase activity is switched on at the intracellular portion. Protein phosphorylation leads to altered cell function via the assembly of other signal proteins. Receptors for growth hormones also belong to the catalytic receptor class. 

The hormone-receptor complexes interact pairwise with DNA. These pairs (dimers) may consist of two identical hormone-receptor complexes (homodimeric form, e.g., with adrenal or gonadal hormones). The thyroid hormone-receptor complex occurs in heterodimeric form and combines with a cis-retinoic acid-receptor complex. 

The receptor protein itself may undergo phosphorylation, with a resultant loss of its ability to activate the associated G-protein. This is one of the mechanisms that contribute to a decrease in sensitivity of a cell during prolonged receptor stimulation by an agonist (desensitization). 

Hormone receptors are of two types. Cell-surface receptors for water-soluble hormones lead to a metabolic response. For example, receptors for the small molecule epinephrine and for the peptide growth hormone are of this type. A protein in the cell membrane binds the hormone and then causes the synthesis of a second messenger, which leads to a metabolic response. 

Metabolic hormones do not exert their effects directly but rather are transduced into an intracellular signal. Transduction refers to the process by which one kind of signal is converted to another. 

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Oxytocin and Vasopressin Receptors. The actions of oxytocin and vasopressin are mediated through their interactions with receptors. Different receptor types as well as different second messenger responses help explain their diverse activities in spite of the hormones stmctural similarities. Thus oxytocin has at least one separate receptor and vasopressin has been shown to have two principal receptor types, and V2. Subclasses of these receptors have been demonstrated, and species differences further compHcate experimental analysis. It is apparent that both oxytocin and receptors function through the GP/1 phosphoHpase C complex (75), while the V2 receptors activate cycHc AMP (76). 

Classification of P2 purinoceptors has been limited by a lack of potent, selective, and bioavailable antagonists. Nonetheless a rational scheme for P2 purinoceptor nomenclature divides P2 receptors into two superfamilies P2Y5 LGIC family having four subclasses and P2Y) a GPCR family having seven subclasses. A third receptor type, designated the P22) is a nonselective ion pore. 

Seghtide readily distinguishes SSTR with picomolar affinity. This compound has nanomolar affinity for SSTR2 and is much weaker at the other subtypes. Ocreotide binds to SSTR, SSTR2 and SSTR receptor types. BIM 23052 [133073-82-2] D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2, and BIM 23056 [150155-61-6], (326) differentiate the SSTR and SSTR2 subtypes. NC4 28B [150155-58-1] (327) and CGP 23996 [86170-12-9] f(Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser-Asn), are SSTR agonists. L 362855 [81710-71-6] (Ala-Phe-Trp-D-Trp-Lys-Thr-Phe), is a... 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

Olfactory receptors have been a subject of great interest (9). Much that has been postulated was done by analogy to the sense of sight in which there are a limited number of receptor types and, as a consequence, only three primary colors. Thus attempts have been made to recognize primary odors that can combine to produce all of the odors that can be perceived. Evidence for this includes rough correlations of odors with chemical stmctural types and the existence in some individuals having specific anosmias. Cross-adaptation studies, in which exposure to one odorant temporarily reduces the perception of a chemically related one, also fit into this hypothetical framework. Implicit in this theory is the idea that there is a small number of well-defined odor receptors, so that eventually the shape and charge distribution of a specific receptor can be learned and the kinds of molecular stmctures for a specified odor can be deduced. 

A critical step in radioprotection involves the IL-1 receptors. Monoclonal antibodies to the type 1 IL-1 receptor block IL-l-induced radioprotection (167). Although this receptor is not present on BM cells, it is present on fibroblasts, which suggests that the effects of IL-1 on stem cells maybe largely indirect and mediated by stromal cell activation (168). Anti-IL-1 receptor (type 1) also sensitizes normal mice to the effects of TBI, which suggests that endogenous IL-1 has an intrinsic radioprotective role. IL-6 induction by IL-1, but not CSF levels, is inhibited, which supports the concept that G-CSF and GM-CSF are insufficient by themselves at radioprotecting stem cells and indicates a contributory role for IL-6. Anti-IL-6 antibody blocks IL-1 and TNF-induced radioprotection and also decreases the intrinsic radioresistance of mice, as does anti-TNF- a (169). 

Compounds which act as antagonists at the receptors for beta sympathetic transmitters (beta blockers) have gained very wide acceptance as antihypertensive agents. It was found subsequent to their introduction that there are two populations of beta receptors the beta-1 receptors are richest in the cardiovascular system whereas beta-2 receptors are mostly found in the bronchi. Lack of receptor-type specificity led to bronchial spasm in some asthmatic individuals on ingestion of the earlier beta blockers. Much of the work outlined below had as its goal the preparation of agents which showed selectivity for beta-1 receptors. 

FIGURE 2.2 Binding and dose-response curves for human calcitonin on human calcitonin receptors type 2. (a) Dose-response curves for microphysiometry responses to human calcitonin in HEK cells (open circles) and binding in membranes from HEK cells (displacement of [,25I]-human calcitonin). Data from [1]. (b) Regression of microphysiometry responses to human calcitonin (ordinates) upon human calcitonin fractional receptor occupancy (abscissae). Dotted line shows a direct correlation between receptor occupancy and cellular response. 

FIGURE 5.6 Calcitonin receptor responses, (a) Real-time melanin dispersion (reduced light transmittance) caused by agonist activation (with human calcitonin) of transfected human calcitonin receptors type II in melanophores. Responses to 0.1 nM (filled circles) and lOnM (open circles) human calcitonin, (c) Dose-response curves to calcitonin in melanophores (open circles) and HEK 293 cells, indicating calcium transient responses (filled circles). 

Central tendency, 226-227 Chemical genomics, 178 Chemical tools, in target-based drug discovery, 178-179 Chemokine C receptor type 1, 133 Chemokine receptors, 6, 44, 53, 129, 132, 177... 

Barr AM, Kinney JW, Hill MN et al (2006) A novel, systemically active, selective galanin receptor type-3 ligand exhibits antidepressant-like activity in preclinical tests. Neurosci Lett 405 111-115... 

Glucocorticoid Receptor GR GCR GRL Nuclear Receptor Subfamily 3, Group C, Member 1 (NR3C1) Glucocorticoid Receptor Type II Mineralocorticoid Receptor MR MCR MRL Nuclear Receptor Subfamily 3, Group C, Member 2 (NR3C2) Glucocorticoid Receptor Type I Aldosterone Receptor... 

Soluble receptor constructs Etanercept This genetically engineered drug consists of the extracellular-part of the TNF-receptor type I and the Fc portion of human IgG. Its application in rheumatoid arthritis mirrors that of infliximab. 

Other names Orexin receptor type 1 Orexin receptor type 2... 

Of the several classes of receptors for endogenous chemical signals [3], two are used as postsynaptic receptors in synaptic transmission ligand-gated ion channels (LGICs) and G protein-coupled receptors (GPCRs Fig. 1). Due to the large number of transmitters and the existence of several receptor types for almost all, postsynaptic receptor activation is the most diversified step of synaptic transmission. Table 1 shows selected neurotransmitter receptors. 

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