Biological Sciences
Intracellular Receptors
Intracellular receptors are proteins located inside the cell that are activated by the binding of specific signaling molecules, such as hormones or neurotransmitters. Once activated, these receptors can directly influence gene expression or other cellular processes, leading to a variety of physiological responses. This mechanism allows for rapid and precise regulation of cellular functions in response to external signals.
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11 Key excerpts on "Intracellular Receptors"
eBook - PDF- Ulo Langel, Benjamin F. Cravatt, Astrid Graslund, N.G.H. von Heijne, Matjaz Zorko, Tiit Land, Sherry Niessen(Authors)
- 2009(Publication Date)
- CRC Press(Publisher)
“A receptor is a cellular macromolecule, or an assembly of macromol-ecules, that is concerned directly and specifically in chemical signaling between and within cells.” Transduction of extracellular signals across the plasma membrane to the intracellular environment is achieved by the interaction of regulatory molecules with specific membrane-spanning cell surface receptors. Interaction of an appropri-ate activating ligand with the receptor at the external face of the cell results in the generation of an intracellular signal. Cell surface receptors are able to distinguish their specific ligands from the multitude of other bioactive factors in the extracel-lular milieu. In response to specific activation, such receptors function in the trans-mission, amplification, and integration of extracellular signals through a variety of intracellular mechanisms to control cellular functioning. Ligand-activated receptors are internalized and in this way, the signal initiated by them can be transferred to different cellular compartments. Based on structural and functional criteria, three broad categories of cell surface receptors that recognize specific molecules may be defined. These comprise (1) ion channels and ligand-gated ion channels, (2) G-protein coupled (7-transmembrane domain) receptors, and (3) enzyme-associated receptors with subunits having one transmembrane domain. However, this classification of receptors is not overwhelm-ing since it does not include several important, additional cell-signaling proteins like cytokine receptors (interleukin receptor family, tumor necrosis factor receptor family, etc.), the immunoglobulin superfamily, Wnt-activated Wnt receptor complex, NGF receptors (p75 or low-affinity nerve growth factor receptor), and others. Cells express receptors that operate through different signaling mechanisms applied by these different receptors, and cross talk often occurs between intracel-lular signaling pathways.
No longer available |Learn more- Gustavo Blanco, Antonio Blanco(Authors)
- 2017(Publication Date)
- Academic Press(Publisher)
Chapter 25 Biochemical Basis of Endocrinology (I) Receptors and Signal Transduction Abstract Cells express receptors, which can be located inside the cell or at the plasma membrane. Intracellular Receptors can be in the nucleus and cytosol. They bind nonpolar or weakly polar molecules (steroid hormones, thyroid hormones, active metabolites of vitamin D, and retinoids), which can easily cross the cell plasma membrane. Once the hormone-receptor complex (HR) forms, it dimerizes and binds to specific DNA sequences (hormone responsive elements), modifying their transcription. Peroxisome proliferator activated receptor (PPAR) is a nuclear receptor that functions as a transcription factor. It regulates metabolic pathways and the cell cycle. Membrane receptors are localized on the cell surface. Upon ligand binding, these receptors undergo conformational changes that are transmitted to protein intermediates of a signal cascade system. They belong to different types: (1) G protein coupled receptors have seven transmembrane segments. G proteins are αβγ heterotrimers, which under basal conditions are inactive, bound to GDP. After binding of the ligand to the receptor, it interacts with a G protein causing the replacement of GDP for GTP, which frees the α-GTP subunit and allows it to activate downstream effectors. The βγ dimer can also act as an intermediate in the signaling process. (2) Tyrosine kinase coupled receptors (TK) consist of an extracellular segment with the ligand-binding site, one transmembrane helix, and a cytoplasmic portion containing kinase activity. Formation of the ligand receptor complex promotes dimerization of the receptor, activates its autophosphorylation and promotes the binding of cell signaling proteins. (3) Receptors associated with extrinsic TK are similar to the ones mentioned previously, but lack the catalytic site. They associate to tyrosine kinase when bound to the ligand
eBook - PDF- Franklyn F. Bolander(Author)
- 2013(Publication Date)
- Academic Press(Publisher)
The other school believes that internalization is a means for delivering the hormone and/or receptor to the cell interior, where it directly exerts some of its biological activity (355). The latter group notes that both hormones and their receptors do exist intracellularly (356). However, since these receptors appear to be identical to those in the plasma membrane (357), they may only represent newly syn-thesized, stored, or recycling receptors. This group also claims that hormones and/or receptors can have direct actions on enzymes (358-361) or on DNA (362). These reports are often countered by the suggestion that these prepa-rations are not pure: contaminating plasma membranes may generate a 790 6. Membrane Receptors second messenger in the presence of the hormone, whereas contaminating enzymes may give rise to spurious activities. Another argument supporting a functional role for processing comes from experiments using lysosomatro-phic alkylamines, which are alkaline compounds taken up by lysosomes (363). These agents block the acidification of the endosome and prevent processing of the hormone-receptor complex. If the biological signal were generated at the cell surface, the inhibition of processing should have no effect on hormone action. On the contrary, these agents do inhibit the activity of some hormones such as EGF. Unfortunately, these same com-pounds are ineffective or only partially effective in other systems. The most interesting example of the latter group is angiotensin II, whose acute release of a second messenger is unaffected by these agents; however, the sustained accumulation of the same mediator is blocked (364). Therefore, in some systems, internalization may help prolong the effects of a hormone. Finally, it is noted that FGF lacks a signal sequence (365) and accumulates in the nucleus (366).
- A. Kleinzeller(Author)
- 2012(Publication Date)
- Elsevier Science(Publisher)
2. Receptor dynamics and cell activation. A general scheme for cell acti-vation is depicted, pointing out the receptor dynamics thought to be involved in the process of cell activation. Very likely, cell responses that are rapidly regulated by neurotransmitters or hormones involve the initial dimerization I microclustering event. Delayed effects of the ligand may be caused by receptor that is internalized in the endosomal organelle. The topography of the en-dosome would permit the intracellular portion of the receptor (designated as 'MA'J to interact with a variety of intracellular constituents located at consid-erable distances from the plasma membrane; the endosomal form of the recep-tor represents an ideal vehicle to carry the receptor rapidly to selected sites of intracellular action. Possibly the intracellular portion of some neurotrans-mitter receptors will be found to contain a kinase domain such as the ones present in receptors for EGF-URO and insulin. The kinase may regulate a variety of enzymatic processes via phosphorylation reactions. In the course of its intracellular migration, the receptor-bearing endosome could ultimately fuse with either lysosomes or other membrane structures (e.g. Golgi elements, nuclear membranes), resulting in further relocation of the receptor. MEMBRANE RECEPTORS 199 cell activation by the receptors for growth factors such as insu-lin or EGF-URO (Schlessinger and Ullrich, 1992; Ullrich and Schlessinger, 1991), the role of receptor dimerization/micro-clustering in the activation of cells by G-protein-coupled recep-tors, such as the one for luteinizing hormone-releasing hormone (LHRH), is still an open question. Once activated by an agonist, the agonist-receptor complex may not only participate in cell surface interactions but may also undergo internalization (i.e. receptor-mediated endocyto-sis, involving clathrin-coated membrane pits) and transloca-tion to other cellular compartments such as the lysosome and the nucleus.
eBook - PDF- Elizabeth H. Holt, Harry E. Peery(Authors)
- 2003(Publication Date)
- Academic Press(Publisher)
Many cells adjust the number of receptors they express in accordance with the abundance of the signal that activates them. Frequent or intense stimula-tion may cause a cell to decrease, or down-regulate , the number of receptors expressed. Conversely, cells may up-regulate receptors in the face of rare or absent stimulation or in response to other signals. Membrane receptors are internalized either alone or bound to their hormones (receptor-mediated endocytosis), and, like other cellular proteins, are broken down and replaced many times over during the lifetime of a cell. Mechanisms of Hormone Action 21 Adjustments in the relative rates of receptor synthesis or degradation may result in either up- or down-regulation of receptor abundance. Cells can also up- or down-regulate receptor function through reversible covalent modifications such as adding or removing phosphate groups. Membrane-associated receptors cycle between the plasma membrane and internal membranes, and their relative abundance on the cell surface can be adjusted by reversibly sequestering them in intracellular vesicles. Although the mammalian organism expresses literally thousands of different receptor molecules that subserve a wide variety of functions in addition to endocrine signaling, our task in understanding receptor physiology is made somewhat simpler by the fact that there are relatively few general patterns of sig-naling. Based on the nucleotide sequence and organization of their genes and the structure of their proteins, receptors—like other proteins—can be organized into families or superfamilies that presumably arose from the same ancient progenitor gene. Even for distantly related receptors the general features of signal transduction follow common broad outlines that are seen with families of molecules that receive and transduce signals in eukaryotic cells of species ranging from yeast to humans.
eBook - ePubThe Endocrine System
Systems of the Body Series
- Joy P. Hinson Raven, Peter Raven, Shern L. Chew, Joy P. Hinson(Authors)
- 2013(Publication Date)
- Churchill Livingstone(Publisher)
2RECEPTORS AND HORMONE ACTION
Chapter objectives After studying this chapter you should be able to:1. Understand that hormones exert their effects by binding to specific receptors in target tissues. 2. Explain what is meant by receptor specificity and affinity and by ligand potency and efficacy. 3. Explain the significance of receptor agonists and antagonists. 4. Categorize common hormones by the types of receptor they bind to. 5. Understand how hormone binding to a receptor brings about changes in cellular activity. 6. Understand the role of second messengers and protein kinases in hormone action.Introduction
All hormones act by binding to receptors in their target cells and by doing so bring about an intracellular response. It is the presence of receptors, which are highly specific binding proteins, that defines the target cells for a hormone: target cells of a hormone are those cells that have receptors for the hormone. The location of these receptors in each cell depends to some extent on the chemical nature of the hormone. Peptide hormones act on receptors located in the cell membrane, while steroid hormones act on Intracellular Receptors. There are many forms of receptor and several different ways in which the action of a hormone binding to a receptor can cause a change in intracellular activity. In this chapter we shall explore the many different forms of hormone action.General characteristics of receptors
Receptor agonists and antagonistsA receptor is a specialized protein, located in the cell membrane, cytoplasm or nucleus of a target cell, which acts to pass on a chemical message. Receptors have binding sites to receive the message and the effect of this interaction is to bring about changes in the receptor which result in the message being passed on to initiate a cellular response. Although the receptor has a ‘specific binding site’ for the physiological chemical message, receptors will usually bind any compound which is structurally similar to the message. Any compound which binds to a receptor is called a ‘ligand’ for that receptor. So a hormone is a naturally occurring ligand for its target cell receptor.
eBook - PDF- M.G. Ord, L.A. Stocken(Authors)
- 1997(Publication Date)
- Elsevier Science(Publisher)
Chapter 6 TALKING TO CELLS-CELL MEMBRANE RECEPTORS AND THEIR MODES OF ACTION Robin F. Irvine Introduction 173 Membrane Receptors 175 Coupling of Receptors to Intracellular Signals 182 Acknowledgments 196 References 196 INTRODUCTION This chapter is essentially about the field of research that we now know as signal transduction or cellular signaling. Currently this field comprises a significant proportion of the world's total research in the life sciences. This is not surprising if one thinks about it. The cells of our tissues are under the constant control of hormones, neurotransmitters, and growth factors, which are telling the cells to do this, do that, stop doing this, do that instead, etc. The great majority of these outside influences—agonists is a useful all-embracing term—are water-soluble. They have to be because they move and work in an aqueous environment. So, when they come up against the hydrophobic cell membrane (plasma membrane) of any cell, they must either be taken up into the cell by an active process (e.g. endocytosis, active transport) which is necessarily slow, or they must bind to a specific recognition site (a receptor) in the plasma membrane, which then registers their presence by sending a chemical signal into the cell. Signal transduction, therefore, is all 173 174 ROBIN F. IRVINE about the nature of these chemical messages, how they are generated after the receptor has bound its ligand (the agonist), and how the cell uses them to alter its function. Because these receptor-generated signals plug-into and modulate the homeostatic control mechanisms of a cell's functions, it is inevitable that in understanding receptor-mediated signal transduction we will understand the fundamentals of cellular function.
eBook - PDF- Franklyn Bolander(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
The latter group notes that both hormones and their receptors do exist intracellularly(66). However, since these receptors appear to be identical to those in the plasma membrane(67), they may only represent newly synthe-sized, stored, or recycling receptors. This group also claims that hormones and/or receptors can have direct actions on nuclei(68), enzymes(69), or DNA(70). These reports are often countered by the suggestion that these preparations are not pure: contaminating plasma membranes may generate a second messenger in the presence of the hormone, while contaminating en-zymes may give rise to spurious activities. Another argument supporting a functional role for processing comes from experiments using lysosomatropic alkylamines, which are alkaline compounds taken up by lysosomes(71). These agents block the acidification of the endosome and prevent processing of the hormone-receptor complex. If the biological signal were generated at the cell
eBook - PDF- Mannfred A. Hollinger(Author)
- 2007(Publication Date)
- CRC Press(Publisher)
Ehrlich based his hypothesis on his experiences with immunochemistry (i.e., the selective neu- tralization of toxin by antitoxin) and chemotherapy (e.g., the treatment of infectious diseases with drugs derived from the German dye industry; see Chapter 10). Ehrlich believed that a drug could have a therapeutic effect only if it has “the right sort of afnity.” He specically wrote, “that combin- ing group of the protoplasmic molecule to which the introduced group is anchored will hereafter be termed receptor.” (It might be appropriate at this point to give credit to the Italian Amedo Avogadro (1776–1856), who coined the term molecules [Latin = “little masses”]). At that time, Ehrlich con- ceived of receptors as being part of “side-chains” in mammalian cells. As we shall see later in this chapter, Ehrlich was not far-off in his visualization. Today, we realize that drug binding to sites that produce pharmacological effects may be part of any cellular constituent, for example, nuclear DNA, mitochondrial enzymes, ribosomal RNA, cytosolic components, and cell membranes and wall, to name the most obvious. Nevertheless, in contemporary pharmacology, some authors and researchers apply a more restricted use of the term receptor, reserving it for protein complexes embedded in, and spanning cellular membranes (e.g., the adrenergic receptor). However, exceptions to this classication system clearly exist, and students should keep this fact in mind. For example, steroids are known to interact with cytosolic receptors that transport them into the nucleus (their site of action), certain anticancer drugs bind to nucleic acids to produce their effects, and bile acids interact with nuclear receptors to modulate cholesterol synthesis. Regardless of how rigid one’s denition of receptor is, receptor theory provides a unifying concept for the explanation of the effect of endogenous or xenobiotic chemicals on biological systems.
eBook - PDF- P. Michael Conn(Author)
- 2013(Publication Date)
- Academic Press(Publisher)
PARTI STIMULUS: RECEPTOR OCCUPANCY AND REGULATION This page intentionally left blank 1 Receptor Regulation by Hormones: Relevance to Secretion and Other Biological Functions ELI HAZUM I. Introduction 4 II. Pituitary Gonadotropin-Releasing Hormone Receptors 4 A. Introductory Remarks 4 B. Internalization of GnRH by Pituitary Gonadotropes 4 C. GnRH Receptor Clustering and Internalization Are Not a Requirement for Gonadotropin Release 7 III. Opiate (Enkephalin) Receptors in Neuroblastoma Cells 8 A. Characterization of Enkephalin Receptors in Neuroblastoma Cells 8 B. Clustering of Enkephalin Receptors 9 C. Mechanism of Cluster Formation: Differences between Clusters Induced by Agonists and Antagonists 11 D. Receptor Pattern and Relationships to Inhibition of Adenylate Cyclase 12 IV. Receptor Internalization as a Possible Mechanism for Biological Responses 13 A. Epidermal Growth Factor 13 B. Studies with Low-Density Lipoprotein 15 V. Receptor Cross-Linking as a Possible Mechanism for Biological Responses 15 A. Insulin and EGF 16 B. Receptor Cross-Linking and Histamine Release 17 C. The Bivalent Ligand Model 17 VI. Conclusions: Models for Hormone Action 18 References 18 CELLULAR REGULATION OF SECRETION AND RELEASE Copyright © 1982 by Academic Press, Inc. All rights of reproduction in any form reserved. ISBN 0-12-185058-7 3 4 Eli Hazum I. INTRODUCTION One of the major goals in modern biology is understanding the mech-anism by which hormones control secretion and other biological func-tions via receptor-mediated events. Recent advances in the field of cell biology have made it possible to study receptor redistribution induced by hormones in living cells. These studies have indicated that, in gen-eral, the occupied receptors for polypeptide hormones appear to be initially distributed uniformly over the cell surface and then rapidly form clusters that are subsequently internalized.
eBook - PDFInsulin Signaling
From Cultured Cells to Animal Models
- George Grunberger, Yehiel Zick(Authors)
- 2002(Publication Date)
- CRC Press(Publisher)
It is also commonly accepted that the internalization rate of the insulin receptor together with the rate of its recycling back to the cell surface, determines the number of receptors present on the cell surface and hence available for insulin binding. This fine tuning of surface insulin receptor number is crucial for the determination of the cell sensitivity to insulin not only in physiological conditions, but also in pathological situations including type 1 diabetes and various forms of insulin resistances (Carpentier, 1994, 1993). Thus, endocytosis is clearly implicated in the regulation of insulin action via a control of insulin degradation and insulin receptor expression on the cell surface. Despite these well accepted functional relevances of insulin receptor internalization, the question of whether this process also permits the access of the kinase-activated insulin receptors to specific intracellular locations thereby allowing interaction with appropriate signaling molecules remains highly controversial (Bevan et al., 1997; Biener et al., 1996; Ceresa et al., 1998; Hamer et al., 2000; Inoue et al., 1998; Kao et al., 1998; Kublaoui et al., 1995; Leconte et al., 1994; Maggi et al., 1998; Navé et al., 1996; Wang et al., 1996) Therefore, elucidation of the mechanisms governing insulin receptor-mediated endocytosis represents an important cornerstone upon which to unravel mechanisms controlling cell growth, functioning and metabolism both in normal and pathological states. The aims of the present review are therefore: a) to consider our present understanding of the ordered sequence of surface and intracellular events paving the entry of the receptor into the cell; b) to disclose the molecular and cellular mechanisms governing the triggering, control and regulation of this process, and c) to envisage the physiological and physiopathological relevance of these events.
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