Hormone receptor

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A hormone receptor is a receptor molecule that binds to a specific hormone. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptors for various ligands, such as fatty acids and prostaglandins. [1] Hormone receptors are of mainly two classes. Receptors for peptide hormones tend to be cell surface receptors built into the plasma membrane of cells and are thus referred to as trans membrane receptors. An example of this is Actrapid. [2] Receptors for steroid hormones are usually found within the protoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. [3] Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

Contents

Hormonal therapy and hormone receptors play a very large part in breast cancer treatment (therapy is not limited to only breast cancer). By influencing the hormones, the cells' growth can be changed along with its function. These hormones can cause cancer to not survive in the human body. [4]

General ligand binding

Signal molecule binds to its hormone receptor, inducing a conformational change in the receptor to begin a signaling cascade that induces a cellular response. Hormone Receptor Binding.png
Signal molecule binds to its hormone receptor, inducing a conformational change in the receptor to begin a signaling cascade that induces a cellular response.

Hormone receptor proteins bind to a hormone as a result of an accumulation of weak interactions. Because of the relatively large size of enzymes and receptors, the large amount of surface area provides the basis for these weak interactions to occur. This binding is actually highly specific because of the complementarity of these interactions between polar, non-polar, charged, neutral, hydrophilic, or hydrophobic residues. Upon binding, the receptor often undergoes a conformational change and may bind further, signaling ligands to activate a signaling pathway. Because of these highly specific and high affinity interactions between hormones and their receptors, very low concentrations of hormone can produce significant cellular response. [5] Receptors can have various different structures depending on the function of the hormone and the structure of its ligand. Therefore, hormone binding to its receptor is a complex process that can be mediated by cooperative binding, reversible and irreversible interactions, and multiple binding sites. [2]

Functions

Transmission of signal

The presence of hormone or multiple hormones enables a response in the receptor, which begins a cascade of signaling. The hormone receptor interacts with different molecules to induce a variety of changes, such as an increase or decrease of nutrient sources, growth, and other metabolic functions. These signaling pathways are complex mechanisms mediated by feedback loops where different signals activate and inhibit other signals. If a signaling pathway ends with the increase in production of a nutrient, that nutrient is then a signal back to the receptor that acts as a competitive inhibitor to prevent further production. [6] Signaling pathways regulate cells through activating or inactivating gene expression, transport of metabolites, and controlling enzymatic activity to manage growth and functions of metabolism. [7]

Intracellular receptors

Intracellular and nuclear receptors are a direct way for the cell to respond to internal changes and signals. Intracellular receptors are activated by hydrophobic ligands that pass through the cellular membrane. All nuclear receptors are very similar in structure, and are described with intrinsic transcriptional activity. Intrinsic transcriptional involves the three following domains: [8] transcription-activating, [9] DNA-binding, [10] and ligand-binding. [11] These domains and ligands are hydrophobic and are able to travel through the membrane. [12] The movement of macromolecules and ligand molecules into the cell enables a complex transport system of intracellular signal transfers through different cellular environments until response is enabled. [13] Nuclear receptors are a special class of intracellular receptor that specifically aid the needs of the cell to express certain genes. Nuclear receptors often bind directly to DNA by targeting specific DNA sequences in order to express or repress transcription of nearby genes. [1]

Cell surface receptors

The extracellular environment is able to induce changes within the cell. Hormones, or other extracellular signals, are able to induce changes within the cell by binding to cell surface receptors also known as transmembrane receptors. [5] This interaction allows the hormone receptor to produce second messengers within the cell to aid response. Second messengers may also be sent to interact with intracellular receptors in order to enter the complex signal transport system that eventually changes cellular function. [2]

G-protein-coupled membrane receptors (GPCR) are a major class of transmembrane receptors. The features of G proteins include GDP/GTP binding, GTP hydrolysis and guanosine nucleotide exchange. [14] [15] When a ligand binds to a GPCR the receptor changes conformation, which makes the intracellular loops between the different membrane domains of the receptor interact with G proteins. This interaction causes the exchange of GDP for GTP, which triggers structural changes within the alpha subunit of the G protein. [16] [15] [14] The changes interrupts the interaction of the alpha subunit with the beta–gamma complex and which results in a single alpha subunit with GTP bound and a beta–gamma dimer. The GTP–alpha monomer interacts with a variety of cellular targets. The beta–gamma dimer also can stimulate enzymes within the cells for example, adenylate cyclase but it does not have as many targets as the GTP–alpha complex. [15]

Aiding gene expression

Hormone receptors can behave as transcription factors by interacting directly with DNA or by cross-talking with signaling pathways. [1] This process is mediated through co-regulators. In the absence of ligand, receptor molecules bind corepressors to repress gene expression, compacting chromatin through histone deacetylatase. When a ligand is present, nuclear receptors undergo a conformational change to recruit various coactivators. These molecules work to remodel chromatin. Hormone receptors have highly specific motifs that can interact with coregulator complexes. [17] This is the mechanism through which receptors can induce regulation of gene expression depending on both the extracellular environment and the immediate cellular composition. Steroid hormones and their regulation by receptors are the most potent molecule interactions in aiding gene expression. [1]

Problems with nuclear receptor binding as a result of shortages of ligand or receptors can have drastic effects on the cell. The dependency on the ligand is the most important part in being able to regulate gene expression, so the absence of ligand is drastic to this process. For example, estrogen deficiency is a cause of osteoporosis and the inability to undergo a proper signaling cascade prevents bone growth and strengthening. Deficiencies in nuclear receptor-mediated pathways play a key role in the development of disease, like osteoporosis. [18]

when a ligand binds to a nuclear receptor, the receptor undergoes a conformational change that causes it to become activated, which in turn affects how much gene expression is regulated.

Classification

Receptors for water-soluble hormones

Water-soluble hormones include glycoproteins, catecholamines, and peptide hormones composed of polypeptides, e.g. thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone and insulin. These molecules are not lipid-soluble and therefore cannot diffuse through cell membranes. Consequently, receptors for peptide hormones are located on the plasma membrane because they have bound to a receptor protein located on the plasma membrane. [19]

Water-soluble hormones come from amino acids and are located and stored in endocrine cells until actually needed. [20]

The main two types of transmembrane receptor hormone receptor are the G-protein-coupled receptors and the enzyme-linked receptors. These receptors generally function via intracellular second messengers, including cyclic AMP (cAMP), cyclic GMP (cGMP), inositol 1,4,5-trisphosphate (IP3) and the calcium (Ca2+)-calmodulin system.

Receptors for lipid-soluble hormones

Cartoon representation of the human hormone estrogen receptor DBD. DNA = orange and blue. DBD of estrogen receptor = white. Zinc atoms = green. Estrogen Receptor DBD.jpg
Cartoon representation of the human hormone estrogen receptor DBD. DNA = orange and blue. DBD of estrogen receptor = white. Zinc atoms = green.

Steroid hormone receptors and related receptors are generally soluble proteins that function through gene activation. Lipid-soluble hormones target specific sequences of DNA by diffusing into the cell. When they have diffused into the cell, they bind to receptors (intracellular), and migrate into the nucleus. [21] Their response elements are DNA sequences (promoters) that are bound by the complex of the steroid bound to its receptor. The receptors themselves are zinc-finger proteins. [22] These receptors include those for glucocorticoids (glucocorticoid receptors), estrogens (estrogen receptors), androgens (androgen receptors), thyroid hormone (T3) (thyroid hormone receptors), calcitriol (the active form of vitamin D) (calcitriol receptors), and the retinoids (vitamin A) (retinoid receptors). Receptor-protein interactions induce the uptake and destruction of their respective hormones in order to regulate their concentration in the body. This is especially important for steroid hormones because many body systems are entirely steroid dependent. [23]

List of hormone receptors

For some of these classes, in any given species (such as, for example, humans), there is a single molecule encoded by a single gene; in other cases, there are several molecules in the class.

Related Research Articles

<span class="mw-page-title-main">G protein-coupled receptor</span> Class of cell surface receptors coupled to G-protein-associated intracellular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.

<span class="mw-page-title-main">G protein</span> Type of proteins

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.

<span class="mw-page-title-main">Hormone</span> Biological signalling molecule

A hormone is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required for the correct development of animals, plants and fungi. Due to the broad definition of a hormone, numerous kinds of molecules can be classified as hormones. Among the substances that can be considered hormones, are eicosanoids, steroids, amino acid derivatives, protein or peptides, and gases.

<span class="mw-page-title-main">Signal transduction</span> Cascade of intracellular and molecular events for transmission/amplification of signals

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Most commonly, protein phosphorylation is catalyzed by protein kinases, ultimately resulting in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.

Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, by phospholipase C (PLC). Together with diacylglycerol (DAG), IP3 is a second messenger molecule used in signal transduction in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. When IP3 binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.

<span class="mw-page-title-main">Steroid hormone</span> Substance with biological function

A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids and sex steroids. Within those two classes are five types according to the receptors to which they bind: glucocorticoids and mineralocorticoids and androgens, estrogens, and progestogens. Vitamin D derivatives are a sixth closely related hormone system with homologous receptors. They have some of the characteristics of true steroids as receptor ligands.

<span class="mw-page-title-main">Neurotransmitter receptor</span> Type of protein

A neurotransmitter receptor is a membrane receptor protein that is activated by a neurotransmitter. Chemicals on the outside of the cell, such as a neurotransmitter, can bump into the cell's membrane, in which there are receptors. If a neurotransmitter bumps into its corresponding receptor, they will bind and can trigger other events to occur inside the cell. Therefore, a membrane receptor is part of the molecular machinery that allows cells to communicate with one another. A neurotransmitter receptor is a class of receptors that specifically binds with neurotransmitters as opposed to other molecules.

<span class="mw-page-title-main">Receptor (biochemistry)</span> Protein molecule receiving signals for a cell

In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and produce physiological responses such as change in the electrical activity of a cell. For example, GABA, an inhibitory neurotransmitter inhibits electrical activity of neurons by binding to GABAA receptors. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway.

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. Second messengers trigger physiological changes at cellular level such as proliferation, differentiation, migration, survival, apoptosis and depolarization.

Intracellular receptors are globular protein receptors located inside the cell rather than on its cell membrane. The word intracellular means "within or inside a cell". Molecules that cross a cell membrane to bind with a receptor are generally nonpolar and may be relatively small. These molecules are also known as ligands. Hormones that use intracellular receptors include thyroid, aldosterone, and steroid hormones.

In biology, cell signaling or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellular life in prokaryotes and eukaryotes. Signals that originate from outside a cell can be physical agents like mechanical pressure, voltage, temperature, light, or chemical signals. Cell signaling can occur over short or long distances, and as a result can be classified as autocrine, juxtacrine, intracrine, paracrine, or endocrine. Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

<span class="mw-page-title-main">Luteinizing hormone/choriogonadotropin receptor</span> Protein-coding gene in the species Homo sapiens

The luteinizing hormone/choriogonadotropin receptor (LHCGR), also lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor (LHR) is a transmembrane receptor found predominantly in the ovary and testis, but also many extragonadal organs such as the uterus and breasts. The receptor interacts with both luteinizing hormone (LH) and chorionic gonadotropins and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning during reproduction.

<span class="mw-page-title-main">Nuclear receptor</span> Protein

In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.

<span class="mw-page-title-main">Guanine nucleotide exchange factor</span> Proteins which remove GDP from GTPases

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of coregulators for nuclear receptors and other transcription factors was previously maintained at the Nuclear Receptor Signaling Atlas website which has since been replaced by the Signaling Pathways Project website.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

Membrane progesterone receptors (mPRs) are a group of cell surface receptors and membrane steroid receptors belonging to the progestin and adipoQ receptor (PAQR) family which bind the endogenous progestogen and neurosteroid progesterone, as well as the neurosteroid allopregnanolone. Unlike the progesterone receptor (PR), a nuclear receptor which mediates its effects via genomic mechanisms, mPRs are cell surface receptors which rapidly alter cell signaling via modulation of intracellular signaling cascades. The mPRs mediate important physiological functions in male and female reproductive tracts, liver, neuroendocrine tissues, and the immune system as well as in breast and ovarian cancer.

References

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  2. 1 2 3 Gammeltoft, S. (1984-10-01). "Insulin receptors: binding kinetics and structure-function relationship of insulin". Physiological Reviews. 64 (4): 1321–1378. doi:10.1152/physrev.1984.64.4.1321. ISSN   0031-9333. PMID   6387730.
  3. ↑ McEwen, B. S.; Kloet, E. R. De; Rostene, W. (1986-10-01). "Adrenal steroid receptors and actions in the nervous system". Physiological Reviews. 66 (4): 1121–1188. doi:10.1152/physrev.1986.66.4.1121. ISSN   0031-9333. PMID   3532143.
  4. ↑ "Understanding Hormone Receptors and What They Do". Breastcancer.org. Retrieved 2017-04-06.
  5. 1 2 Nelson 1, Cox 2, Lehninger 3. Principles of Biochemistry. New York: Worth. p. 81.{{cite book}}: CS1 maint: multiple names: authors list (link)
  6. ↑ Mullur, Rashmi; Liu, Yan-Yun; Brent, Gregory A. (2014-04-01). "Thyroid Hormone Regulation of Metabolism". Physiological Reviews. 94 (2): 355–382. doi:10.1152/physrev.00030.2013. ISSN   0031-9333. PMC   4044302 . PMID   24692351.
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  10. ↑ Follis, Ariele Viacava; Llambi, Fabien; Ou, Li; Baran, Katherine; Green, Douglas R.; Kriwacki, Richard W. (2014-06-01). "The DNA-binding domain mediates both nuclear and cytosolic functions of p53". Nature Structural & Molecular Biology. 21 (6): 535–543. doi:10.1038/nsmb.2829. ISSN   1545-9993. PMC   4134560 . PMID   24814347.
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  13. ↑ Stockert, R. J. (1995-07-01). "The asialoglycoprotein receptor: relationships between structure, function, and expression". Physiological Reviews. 75 (3): 591–609. doi:10.1152/physrev.1995.75.3.591. ISSN   0031-9333. PMID   7624395.
  14. 1 2 Principles of endocrinology and hormone action. Belfiore, Antonino,, LeRoith, Derek, 1945-. Cham. ISBN   9783319446752. OCLC   1021173479.{{cite book}}: CS1 maint: others (link)
  15. 1 2 3 Kleine, Bernhard; Rossmanith, Winfried G. (2016), "Hormone Receptors", Hormones and the Endocrine System, Springer International Publishing, pp. 247–259, doi:10.1007/978-3-319-15060-4_8, ISBN   9783319150598
  16. ↑ F., Bolander, Franklyn (1989). Molecular endocrinology. San Diego: Academic Press. ISBN   978-0121112301. OCLC   18324100.{{cite book}}: CS1 maint: multiple names: authors list (link)
  17. ↑ Vasudevan, Nandini; Ogawa, Sonoko; Pfaff, Donald (2002-01-10). "Estrogen and Thyroid Hormone Receptor Interactions: Physiological Flexibility by Molecular Specificity". Physiological Reviews. 82 (4): 923–944. doi:10.1152/physrev.00014.2002. ISSN   0031-9333. PMID   12270948. S2CID   28649627.
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  22. ↑ "Steroid Hormone Receptors and their Response Elements". Archived from the original on 2006-12-30. Retrieved 2006-05-01.
  23. ↑ Gimpl, Gerald; Fahrenholz, Falk (2001-04-01). "The Oxytocin Receptor System: Structure, Function, and Regulation". Physiological Reviews. 81 (2): 629–683. doi:10.1152/physrev.2001.81.2.629. ISSN   0031-9333. PMID   11274341. S2CID   13265083.
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