Hormone-Receptor Interaction

Figure 13.22 Hormone-receptor interactions involving the domain-domain linker region in the receptor, (a) Interactions between the growth hormone (red) and the growth hormone receptor (blue) linker region. Glu 127 of the receptor forms a salt bridge to Arg 167 in the hormone, (b) The same interaction area in the growth hormone (red)-prolactin receptor (green) complex. The displacement of the linker region due to differences in the domain orientations have brought Asp 124 in the prolactin receptor into contact with Arg 167 of the hormone. (Adapted from W. Somers et al.. Nature 372 478-481, 1994.)...

A target cell is defined by its ability to selectively bind a given hormone to its cognate receptor. Several biochemical feamres of this interaction are important in order for hormone-receptor interactions to be physio-... 

Angiotensin II binds to specific adrenal cortex glomerulosa cell receptors. The hormone-receptor interaction does not activate adenylyl cyclase, and cAMP does not appear to mediate the action of this hormone. The actions of angiotensin II, which are to stimulate the conversion of cholesterol to pregnenolone and of corticosterone to 18-hydroxycorticosterone and aldosterone, may involve changes in the concentration of intracellular calcium and of phospholipid metabolites by mechanisms similar to those described in Chapter 43. 

First described in 1926 by Perrin [16], the theory was greatly expanded by Weber [17], who developed the first instrumentation for the measurement of FP. Dandliker [18] expanded FP into biological systems such as antigen-antibody reactions and hormone-receptor interactions. Jolley [19] developed FP into a commercial system for monitoring of therapeutic drug levels and the detection of drugs of abuse in human body fluids. 

The objective of such studies is to measure the affinity, capacity and specificity of the hormone-receptor interaction [3, 7], Measurements of affinity and capacity are... 

Fig. 1.5. Activation of the native receptor by thehormone. The hormone-receptor interaction determines a very strong bond that attracts distant amino acid residues, which alters the three-dimensional structure of the receptor. As a consequence, the receptor loses its affinity for the proteins that were originally close but that no longer find their zones of contact with the receptor. Simultaneously, the receptor reorganizes other hormone-dependent zones it acquires dimerization capacity and exhibits a capacity to bind to DNA and to transcription factors. The interaction with antiestrogens also produces a conformational change, which can give rise or not to the formation of dimers, in any case with a different conformation...

The dimer of the hormone-receptor complex should scrutinize an infinity of sequences before finding its FIRE. The role of the hormone in the recognition of the HRE seems to be that of dramatically increasing the velocity of DNA sequence recognition, that is to say, it binds and disconnects more quickly to sequences of nonspecific DNA. When it finds the sequence of its HRE, a bond of affinity is formed that is similar to that of hormone-receptor interaction (Kd in the nM range). 

The normal form of interaction between receptor and DNA requires the hormone to have broken the native structure of the receptor and the dimer to have been formed. That is to say, the receptor-DNA interaction comes after the hormone-receptor interaction. Nevertheless, situations have been described in vitro in which the receptor is able to be previously associated to the HRE. This situation occurs in vivo for the thyroid hormone receptors, in which case it seems that the hormone-free dimer acts as an expression repressor of genes dependent on these hormones (Evans et al. 1988). The arrival of the hormone activates the dimer in situ and inverts its role as regulator. 

Vasudevan N, Ogawa S, Pfaff D (2002) Estrogen and thyroid hormone receptor interactions physiological flexibility by molecular specificity. Physiol Rev 82 923... 

Like FRET, today BRET is predominantly used in biological sciences, especially in the monitoring of protein-protein interactions such as hormone-receptor interaction [223, 224] and protein-DNA interaction in living systems. However, BL resonance energy transfer can also be applied in immunoassays by using for instance a peptide-tagged luciferase and a fluorescein-labeled antipeptide antibody [225]. The development of more BRET assays for small-molecule analytes is thus awaited. 

Very little is known about the motions of lipid bilayers at elevated pressures. Of particular interest would be the knowledge of the eifect of pressure on lateral diifusion, which is related to biological functions such as electron transport and some hormone-receptor interactions. However, pressure eifects on lateral diifusion of pure lipid molecules and of other membrane components have yet to be studied carefully. 

In addition, any rational approach to peptide hormone and neurotransmitter design must ultimately depend on the application of physical-chemical principles of conformation and structure, the use of various spectroscopic methods (especially nuclear magnetic resonance, circular dlchrolsm, and Raman spectroscopies. X-ray analysis where possible, etc.), and an understanding of the nature of a hormone-receptor Interaction In physical-chemical terms. Here again the use of conformatlonally restricted peptide structures Is critical (, 2. Recently we have... 

A. De Lean, P. J. Munson, D. Rodbard (1979). Multivalent ligand binding to multisubsite receptors application to hormone-receptor interactions. Mol. Pharmacol. 15 60-70. 

E. N. Cheung (1995). Thyroid hormone action determination of hormone-receptor interaction using structural analogs and molecular modeling. Trends Pharmacol. Sci. 6 31-34. 

Fig. 12. A pictorial representation of adenylate cyclase and hormone receptors interacting with a membrane. The GTP control component is also shown. The different hormone receptors may not interact directly with the adenylate cyclase and may be diffusing freely in the membrane until a hormone is bound.

A number of other, more specialized systems are available to the reproductive toxicologist to answer specific mechanistic questions. In particular, the hormonal control of reproductive function and its perturbation by toxicants have received much attention. Such investigations can use intact cells to investigate the downstream consequences of toxicants on hormone-receptor interactions or use cells that respond to specific hormones (e.g., the MCF-7 breast cancer cell line and estrogen Soto et al., 1995). Receptor biology/ligand binding can be examined in membrane preparations of specific cell types or in recombinant cell systems (e.g., human and yeast cells Klein et al.,... 

Pellegrini, M., Mierke, D.F. (1999). Structural characterization of peptide hormone/receptor interactions by NMR spectroscopy. Biopolymers (Peptide Sci.), 51, 208-220. 

The locus of the encounter between hormone and receptor may be extracellular, cytosolic, or nuclear, depending on the hormone type. The intracellular consequences of hormone-receptor interaction are of at least six general types (1) a change in membrane potential results from the opening or closing of a hormone-gated... 

The retro-peptide bond is a true isosteric peptide bond surrogate and as such may offer an important tool to study topics such as the functional role of the peptide backbone in peptide hormone-receptor interactions, and modulation of metabolic stability and bioavailability. Partially modified retro-inverso-peptides (PMRI-peptides) (e.g., 2-4, 7 Scheme 1) result from a retro-inverso transformation of one or several peptide bonds in an amino- and carboxy-free peptide (e.g., 5 Scheme 1). Evidently, partial or exhaustive retro-inverso transformations result in the introduction of two non-amino acid residues into the... 

In the following sections we discuss how hormones are synthesized, transported, and degraded. Then we explore basic aspects of hormone-receptor interaction and the... 

Nishi, S., Nakabayashi, K., Kobilka, B., and Hsueh, A. J. (2002). The ectodomain of the luteinizing hormone receptor interacts with exoloop 2 to constrain the transmembrane region Studies using chimeric human and fly receptors. /. Biol. Chem. 277, 3958-3964. 

As indicated earlier, the intent of this section was not to be global with respect to the scope of its coverage, but rather to discuss in general terms some considerations common to the study of ligands which interact with membrane receptors and, thereby, elicit post-binding events. Many of the examples chosen have been drawn from my experience with the follitropin-gonadal receptor system, but they provide instances of problems, concerns and caveats in use of techniques and interpretation of results that are common to this particular field of study. The reader is referred to the specific examples of hormone receptor interactions to follow, wherein aspects of the problems not germaine to this section, such as, for example, techniques for purification of solubilized receptors, are considered in detail. 

Hormone-Receptor Interaction Molecular Aspects Levey, G. S., Ed. Dekker 1976 265. 

There are many ways in which hormone-receptor interactions may be studied, the classic method being the Scatchard technique, named in honor of George Scatchard. This technique is applicable to any protein-small molecule interaction, and it provides a means of determining the heterogeneity of binding sites, dissociation constants, and the number of binding sites per receptor unit. The last may be a protein molecule, a cell, a cell membrane fragment, or a unit volume of cytosol with a known protein content. 

Figure 16.18 Overview of signal transmission from hormone-receptor interaction on the outside cell surface to cAMP production on the cytosol side of the membrane through stimulation of adenylate cyclase. Hs is the stimulatory hormone, and R is its receptor. Gs is the stimulatory G protein. is an inhibitory hormone, and Rj is its cell surface receptor. Gj is the inhibitory G protein. The last inhibits adenylate cyclase when combined with GTP.

Less well-defined but particularly important in terms of the function of non-neuronal cells are so-called receptor-operated channels [6,7]. By definition these are channels in the plasma membrane which open in response to hormone-receptor interaction without a change in membrane potential. The mechanism of their opening may either be by a direct coupling of receptor (possibly via a G protein) with the channel, or by an indirect coupling via the generation of an intracellular messenger such as cAMP or the putative messenger, inositol 1,3,4,5-tetrakisphosphate. 

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