Receptor (biochemistry)

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An example of membrane receptors.
Ligands, located outside the cell
Ligands connect to specific receptor proteins based on the shape of the active site of the protein.
The receptor releases a messenger once the ligand has connected to the receptor. Receptor (Biochemistry).svg
An example of membrane receptors.
  1. Ligands, located outside the cell
  2. Ligands connect to specific receptor proteins based on the shape of the active site of the protein.
  3. The receptor releases a messenger once the ligand has connected to the receptor.

In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. [1] These signals are typically [nb 1] chemical messengers, which bind to a receptor, they cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. [2] 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. [2] In this sense, a receptor is a protein-molecule that recognizes and responds to endogenous chemical signals. For example, an acetylcholine receptor recognizes and responds to its endogenous ligand, acetylcholine. However, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters, and ion channels.[ citation needed ]

Biochemistry study of chemical processes in living organisms

Biochemistry, sometimes called biological chemistry, is the study of chemical processes within and relating to living organisms. Biochemical processes give rise to the complexity of life.

Pharmacology Branch of biology concerning drugs

Pharmacology is the branch of biology concerned with the study of drug or medication action, where a drug can be broadly defined as any man-made, natural, or endogenous molecule which exerts a biochemical or physiological effect on the cell, tissue, organ, or organism. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.

Protein Biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

Contents

Receptor proteins can be classified by their location. Transmembrane receptors include ion channel-linked (ionotropic) receptors, G protein-linked (metabotropic) hormone receptors, and enzyme-linked hormone receptors. [1] Intracellular receptors are those found inside the cell, and include cytoplasmic receptors and nuclear receptors. [1] A molecule that binds to a receptor is called a ligand, and can be a protein or peptide (short protein), or another small molecule such as a neurotransmitter, hormone, pharmaceutical drug, toxin, or parts of the outside of a virus or microbe. The endogenously designated -molecule for a particular receptor is referred to as its endogenous ligand. E.g. the endogenous ligand for the nicotinic acetylcholine receptor is acetylcholine but the receptor can also be activated by nicotine [3] [4] and blocked by curare. [5] Receptors of a particular type are linked to a specific cellular biochemical pathways that correspond to the signal. While numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure. This has been analogously compared to how locks will only accept specifically shaped keys. When a ligand binds to a corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway.

Ligand-gated ion channel type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

G protein-coupled receptor a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and cellular responses

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein–linked receptors (GPLR), constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times.

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. There are two main classes of hormone receptors. 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 insulin. Receptors for steroid hormones are usually found within the cytoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

Structure

Transmembrane receptor:E=extracellular space; I=intracellular space; P=plasma membrane Transmembrane receptor.svg
Transmembrane receptor:E=extracellular space; I=intracellular space; P=plasma membrane

The structures of receptors are very diverse and include the following major categories, among others:

Alpha helix type of secondary structure

The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group donates a hydrogen bond to the backbone C=O group of the amino acid located three or four residues earlier along the protein sequence.

Receptor tyrosine kinase

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non receptor tyrosine kinases which do not possess transmembrane domains.

An enzyme-linked receptor, also known as a catalytic receptor, is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protein possessing both enzymatic catalytic and receptor functions.

Membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents, detergents, and/or affinity purification.

The structures and actions of receptors may be studied by using biophysical methods such as X-ray crystallography, NMR, circular dichroism, and dual polarisation interferometry. Computer simulations of the dynamic behavior of receptors have been used to gain understanding of their mechanisms of action.

Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and their complexes. The field was pioneered by Richard R. Ernst and Kurt Wüthrich at the ETH, and by Ad Bax, Marius Clore, and Angela Gronenborn at the NIH, among others. Structure determination by NMR spectroscopy usually consists of several phases, each using a separate set of highly specialized techniques. The sample is prepared, measurements are made, interpretive approaches are applied, and a structure is calculated and validated.

Circular dichroism (CD) is dichroism involving circularly polarized light, i.e., the differential absorption of left- and right-handed light. Left-hand circular (LHC) and right-hand circular (RHC) polarized light represent two possible spin angular momentum states for a photon, and so circular dichroism is also referred to as dichroism for spin angular momentum. This phenomenon was discovered by Jean-Baptiste Biot, Augustin Fresnel, and Aimé Cotton in the first half of the 19th century. It is exhibited in the absorption bands of optically active chiral molecules. CD spectroscopy has a wide range of applications in many different fields. Most notably, UV CD is used to investigate the secondary structure of proteins. UV/Vis CD is used to investigate charge-transfer transitions. Near-infrared CD is used to investigate geometric and electronic structure by probing metal d→d transitions. Vibrational circular dichroism, which uses light from the infrared energy region, is used for structural studies of small organic molecules, and most recently proteins and DNA.

Computer simulation simulation, run on a single computer, or a network of computers, to reproduce behavior of a system; modeling a real physical system in a computer

Computer simulation is the reproduction of the behavior of a system using a computer to simulate the outcomes of a mathematical model associated with said system. Since they allow to check the reliability of chosen mathematical models, computer simulations have become a useful tool for the mathematical modeling of many natural systems in physics, astrophysics, climatology, chemistry, biology and manufacturing, human systems in economics, psychology, social science, health care and engineering. Simulation of a system is represented as the running of the system's model. It can be used to explore and gain new insights into new technology and to estimate the performance of systems too complex for analytical solutions.

Binding and activation

Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action in the following equation, for a ligand L and receptor, R. The brackets around chemical species denote their concentrations.

In a chemical reaction, chemical equilibrium is the state in which both reactants and products are present in concentrations which have no further tendency to change with time, so that there is no observable change in the properties of the system. Usually, this state results when the forward reaction proceeds at the same rate as the reverse reaction. The reaction rates of the forward and backward reactions are generally not zero, but equal. Thus, there are no net changes in the concentrations of the reactant(s) and product(s). Such a state is known as dynamic equilibrium.

In chemistry, the law of mass action is the proposition that the rate of a chemical reaction is directly proportional to the product of the activities or concentrations of the reactants. It explains and predicts behaviors of solutions in dynamic equilibrium. Specifically, it implies that for a chemical reaction mixture that is in equilibrium, the ratio between the concentration of reactants and products is constant.

One measure of how well a molecule fits a receptor is its binding affinity, which is inversely related to the dissociation constant Kd. A good fit corresponds with high affinity and low Kd. The final biological response (e.g. second messenger cascade, muscle-contraction), is only achieved after a significant number of receptors are activated.

Affinity is a measure of the tendency of a ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate its receptor.

Agonists versus antagonists

Efficacy spectrum of receptor ligands. Efficacy spectrum.png
Efficacy spectrum of receptor ligands.

Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist:

Note that the idea of receptor agonism and antagonism only refers to the interaction between receptors and ligands and not to their biological effects.

Constitutive activity

A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity". [9] The constitutive activity of a receptor may be blocked by an inverse agonist. The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive activity of the cannabinoid receptor.

The GABAA receptor has constitutive activity and conducts some basal current in the absence of an agonist. This allows beta carboline to act as an inverse agonist and reduce the current below basal levels.

Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors).

Theories of drug-receptor interaction

Occupation

The central dogma of receptor pharmacology is that a drug effect is directly proportional to the number of receptors that are occupied.[ citation needed ] Furthermore, a drug effect ceases as a drug-receptor complex dissociates.

Ariëns & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of ligands bound to receptors. [10] [11]

Rate

In contrast to the accepted Occupation Theory, Rate Theory proposes that the activation of receptors is directly proportional to the total number of encounters of a drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, not the number of receptors occupied: [12]

Induced-fit

As a drug approaches a receptor, the receptor alters the conformation of its binding site to produce drug—receptor complex.

Spare Receptors

In some receptor systems (e.g. acetylcholine at the neuromuscular junction in smooth muscle), agonists are able to elicit maximal response at very low levels of receptor occupancy (<1%). Thus, that system has spare receptors or a receptor reserve. This arrangement produces an economy of neurotransmitter production and release. [8]

Receptor-regulation

Cells can increase (upregulate) or decrease (downregulate) the number of receptors to a given hormone or neurotransmitter to alter their sensitivity to different molecule. This is a locally acting feedback mechanism.

Examples and Ligands

The ligands for receptors are as diverse as their receptors. GPCRs (7TMs) are a particularly vast family, with at least 810 members. There are also LGICs for at least a dozen endogenous ligands, and many more receptors possible through different subunit compositions. Some common examples of ligands and receptors include: [14]

Ion channels and G protein coupled receptors

Some example ionitropic (LGIC) and metabotropic (GPCRs) receptors are shown in the table below. The chief neurotransmitters are glutamate and GABA; other neurotransmitters are neuromodulatory. This list is by no means exhaustive.

Endogenous Ligand Ion channel receptor (LGIC) G protein coupled receptor (GPCR)
Receptors Ion current [nb 2] Exogenous LigandReceptors G protein Exogenous Ligand
Glutamate iGluRs: NMDA,
AMPA, and Kainate receptors
Na+, K+, Ca2+ [14] Ketamine Glutamate receptors: mGluRs Gq or Gi/o-
GABA GABAA
(including GABAA-rho)
Cl > HCO3 [14] Benzodiazepines GABAB receptor Gi/o Baclofen
Acetylcholine nAChR Na+, K+, Ca2+ [14] Nicotine mAChR Gq or Gi Muscarine
Glycine Glycine receptor (GlyR)Cl > HCO3 [14] Strychnine ---
Serotonin 5-HT3 receptor Na+, K+ [14] Cereulide 5-HT1-2 or 4-7 Gs, Gi/o or Gq-
ATP P2X receptors Ca2+, Na+, Mg2+ [14] BzATP[ citation needed ] P2Y receptors Gs, Gi/o or Gq-
Dopamine No ion channels[ citation needed ]-- Dopamine receptor Gs or Gi/o-

Enzyme linked receptors

Enzyme linked receptors include receptor tyrosine kinases (RTK), serine/threonine-specific protein kinase, as in bone morphogenetic protein and guanylate cyclase, as in atrial natriuretic factor receptor. Of the RTKs, 20 classes have been identified, with 58 different RTKs as members. Some examples are shown below:

RTK Class/Receptor FamilyMemberEndogenous LigandExogenous Ligand
I EGFR EGF Gefitinib
II Insulin Receptor Insulin Chaetochromin
IV VEGFR VEGF Lenvatinib

Intracellular Receptors

Receptors may be classed based on their mechanism or on their position in the cell. 4 examples of intracellular LGIC are shown below:

ReceptorLigandIon current
cyclic nucleotide-gated ion channels cGMP (vision), cAMP and cGTP (olfaction)Na+, K+ [14]
IP3 receptor IP3 Ca2+ [14]
Intracellular ATP receptors ATP (closes channel) [14] K+ [14]
Ryanodine receptor Ca2+Ca2+ [14]

Role in genetic disorders

Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the hormone is produced at decreased level; this gives rise to the "pseudo-hypo-" group of endocrine disorders, where there appears to be a decreased hormonal level while in fact it is the receptor that is not responding sufficiently to the hormone.

In the immune system

The main receptors in the immune system are pattern recognition receptors (PRRs), toll-like receptors (TLRs), killer activated and killer inhibitor receptors (KARs and KIRs), complement receptors, Fc receptors, B cell receptors and T cell receptors. [15]

See also

Notes

  1. In the case of the Rhodopsin receptor, the input is a photon, not a chemical
  2. Different LGICs conduct currents of different ions. This is accomplished with selectivity filters, as with the selectivity filter of the K+ channel

Related Research Articles

Signal transduction cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell

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 catalyzed by protein kinases, which ultimately results 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 as a signaling pathway.

Acetylcholine receptor

An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.

Neurotransmitter receptor

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 and along the membrane we can find 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.

Agonist chemical substance which, upon binding to a receptor, leads to its activation

An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist, and an inverse agonist causes an action opposite to that of the agonist.

Excitatory synapse A synapse in which an action potential in the presynaptic cell increases the probability of an action potential occurring in the postsynaptic cell.

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travel, each neuron often making numerous connections with other cells. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

Receptor antagonist class of pharmacological agents

A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.

Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms. Pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug. Both together influence dosing, benefit, and adverse effects. Pharmacodynamics is sometimes abbreviated as PD and pharmacokinetics as PK, especially in combined reference.

Inverse agonist agent in biochemistry

In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.

<i>beta</i>-Endorphin chemical compound

β-Endorphin is an endogenous opioid neuropeptide and peptide hormone that is produced in certain neurons within the central nervous system and peripheral nervous system. It is one of three endorphins that are produced in humans, the others of which include α-endorphin and γ-endorphin.

GABA<sub>A</sub> receptor it is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid, the major inhibitory neurotransmitter in the central nervous system.

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl through its pore. Cl- will flow out of the cell if the internal voltage is less than resting potential and Cl- will flow in if it is more than resting potential. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring. The reversal potential of the GABAA-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABAB IPSP (-100 mV).

Neuropharmacology is the study of how drugs affect cellular function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

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 such as proliferation, differentiation, migration, survival, and apoptosis.

The action of drugs on the human body is called pharmacodynamics, and what the body does with the drug is called pharmacokinetics. The drugs that enter the human tend to stimulate certain receptors, ion channels, act on enzymes or transporter proteins. As a result, they cause the human body to react in a specific way.

Ligand (biochemistry) Ligand in biochemistry

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure. The instance of binding occurs over an infinitesimal range of time and space, so the rate constant is usually a very small number.

Nuclear receptor InterPro Family

In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.

A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine.

Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that would mediate drug action at the beginning of the 20th century. A J Clark was the first to quantify drug-induced biological responses (using an equation described f-mediated receptor activation. So far, nearly all of the quantitative theoretical modelling of receptor function has centred on ligand-gated ion channels and GPCRs.

Cell surface receptor

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.

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