Dalam biokimia, reseptor adalah molekul protein yang menerima sinyal kimia dari luar sel yang mengarahkan

kegiatan sel seperti membelah atau mengizinkan molekul tertentu untuk masuk atau keluar sel. Reseptor dapat terikat pada membran sel, sitoplasma, atau nukleus, yang masing-masing hanya dapat dilekati oleh jenis molekul sinyal tertentu. Molekul pemberi sinyal yang melekat pada suatu reseptor disebut ligan, yang dapat berupa suatu peptida atau molekul kecil lain seperti neurotransmiter, hormon, obat, atau toksin. Membrane bound receptor these are proteins that are associated with the cell membrane. they can span across the membrane and can transmit a signal from outside the cell to inside the cell. outside the cell, a signal (like a hormone for example) will bind to the receptor. This causes the receptor to change it's shape. The shape change is detected inside the cell. It is the shape change that is the transmission of the signal from the outside to the inside. Inside the cell, other proteins can interact with the receptor in it's new shape and be turned 'on' to continue the signal pathway. In biochemistry and pharmacology, a receptor is a protein molecule usually found inside or on the surface of a cell, that receives chemical signals from outside the cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, e.g. change in the electrical activity of the cell. In this sense, a receptor is a protein molecule that recognises and responds to endogenous chemical signals, e.g. the acetylcholine receptor recognised 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. Receptor proteins are embedded in either the cell's plasma membrane (cell surface receptors), the cytoplasm(cytoplasmic receptors), or in the nucleus (nuclear receptors). A molecule that binds to a receptor is called a ligand, and can be a peptide (short protein) or another small molecule such as a neurotransmitter, hormone, pharmaceutical drug, or toxin. 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 and blocked by curare. Each receptor is linked to a specific cellular biochemical pathway. While numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure, much like how locks will only accept specifically shaped keys. When a ligand binds to its corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway.
Contents
[hide]

1 Structure 2 Binding and activation

o o o

2.1 Agonists versus antagonists 2.2 Constitutive activity 2.3 Theories of drug receptor interaction

2.3.1 Occupation theory 2.3.2 Rate theory 2.3.3 Induced fit theory 2.3.4 Spare receptors

3 Receptor regulation 4 Ligands

o o

4.1 Extracellular 4.2 Intracellular

5 Role in genetic disorders 6 In the immune system 7 See also 8 References 9 External links

Structure[edit]

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

The structures of receptors are very diverse and can broadly be classified into the following categories: Type 1: L (ionotropic receptors) These receptors are typically the targets of fast neurotransmitters such as acetylcholine (nicotinic) and GABA and activation of these receptor results in changes in ion movement across the membrane. They have a hetero structure. Each subunit consists of the extracellular ligand-binding domain and a transmembrane domain where the transmembrane domain in turn includes four transmembrane alpha helixes. The ligand binding cavities are located at the interface between the subunits. Type 2: G protein-coupled receptors (metabotropic) This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e.g. dopamine, metabotropic glutamate. They are composed of seven transmembrane alpha helices. The loops connecting the alpha helices form extracellular and intracellular domains. The binding site for larger peptidic ligands is usually located in the extracellular domain whereas the binding site for smaller non-peptidic ligands is often located between [1] the seven alpha helices and one extracellular loop. These receptors are coupled to different intracellular effector systems via G-proteins. Type 3: kinase linked and related receptors - These receptors are composed of an extracellular domain containing the ligand binding site and an an intracellular domain, often with enzymatic function, linked by a single transmembrane alpha helix. e.g. the insulin receptor.

Type 4: nuclear receptors While they are called nuclear receptors, these are actually located in the cytosol and migrate to the nucleus after binding with their ligands. They are composed of a C-terminal ligand binding region, a core DNA-binding domain (DBD) and an N-terminal domain that contains the AF1(activation function 1) region. The core region has two zinc fingers that are responsible for recognising the DNA sequences specific to this receptor. The N-terminal interacts with other cellular transcription factors in a ligand independent manner and depending on these interactions it can modify the binding/activity of the receptor. Steroid and thyroid hormone recptors are examples of [2] such receptors.

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 mechanism of action.

Binding and activation[edit]

Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action.

(the brackets stand for concentrations) One measure of how well a molecule fits a receptor is the 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 the ligand to bind to its receptor. Efficacy is the measure of the bound ligand to activate the receptor.

Agonists versus antagonists[edit]

Efficacy spectrum of receptor ligands.

Not every ligand that binds to a receptor also activates the receptor. The following classes of ligands exist: (Full) agonists are able to activate the receptor and result in a maximal biological response. The natural endogenous ligand with the greatest efficacy for a given receptor is by definition a full agonist (100% efficacy).

Partial agonists do not activate receptors with maximal efficacy, even with maximal binding, causing responses which are partial compared to those of full agonists (efficacy between 0 and 100%). Antagonists bind to receptors but do not activate them. This results in receptor blockade, inhibiting the binding of agonists and inverse agonists. Receptor antagonists can be competitive (or reversible), and compete with the agonist for the receptor, or they can be irreversible antagonists that form covalent bonds with the receptor and completely block it. The protein pump inhibitor omeprazole is an example of an irreversible antagonist. The effects of irreversible antagonism can only be reversed by synthesis of new receptors. Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity (negative efficacy). Allosteric modulators: These do not bind to the agonist binding site of the receptor but instead on specific allosteric binding sites, through which they modify the effect of the agonist, e.g. benzodiazepines (BZDs) bind to the BZD site on the GABA-A receptor and potentiate the effect of endogenous GABA.

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

Constitutive activity[edit]
A receptor which is capable of producing its biological response in the absence of a [3] bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist. The anti-obesity drugs rimonabant and tarannabant 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. 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[edit]

Occupation theory[edit]
The central dogma of receptor pharmacology is that drug effect is directly proportional to number of receptors occupied. Furthermore, drug effect ceases as drug-receptor complex dissociates. Arins & Stephenson introduced the terms "affinity" & "efficacy" to describe the [4][5] action of ligands bound to receptors. Affinity: ability of the drug to combine with receptor to create drug-receptor complex Efficacy: ability of the drug-receptor complex to initiate a response

Rate theory[edit]
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 the

drug with its receptors per unit time. Pharmacological activity is directly proportional [6] to the rates of dissociation and association, not number of receptors occupied: Agonist: drug with fast association & fast dissociation Partial agonist: drug with intermediate association & intermediate dissociation Antagonist: drug with fast association & slow dissociation

Induced fit theory[edit]

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

Spare receptors[edit]
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 the system has spare receptors or receptor reserve. This [7] arrangement produces an economy of neurotransmitter production and release.

Receptor regulation[edit]
Cells can increase (upregulate) or decrease (downregulate) the number of receptors to a given hormone or neurotransmitter to alter its sensitivity to this molecule. This is a locally acting feedbackmechanism. Change in the receptor conformation such that binding of the agonist does not activate the receptor. This is seen with ion channel receptors. Uncoupling of the receptor effector molecules is seen with G-protein couple receptor. Receptor sequestration (internalization).
[8]

e.g. in the case of hormone receptors.

Ligands[edit]
The ligands for receptors are as diverse as their receptors. Examples include:
[9]

Extracellular[edit]
Receptor Ligand Ion current

Nicotinic acetylcholine receptor

Acetylcholine, Nicotine

Na , K , 2+[9] Ca

Glycine receptor (GlyR)

Glycine, Strychnine

Cl > [9] HCO 3

GABA receptors: GABA-A, GABA-C

GABA

Cl > [9] HCO 3

Glutamate receptors: NMDA receptor, AMPA receptor, and Kainate receptor

Glutamate

Na , K , 2+ [9] Ca

5-HT3 receptor

Serotonin

Na , K

+ [9]

P2X receptors

ATP

Ca , Na , 2+ [9] Mg

2+

Intracellular[edit]
Receptor Ligand Ion current

cyclic nucleotide-gated ion channels

cGMP (vision), cAMP and cGTP (olfaction)

Na , + [9] K

IP3 receptor

IP3

Ca

2+ [9]

Intracellular ATP receptors

ATP (closes channel)

[9]

+ [9]

Ryanodine receptor

Ca

2+

Ca

2+ [9]

Role in genetic disorders[edit]

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[edit]

Main article: Immune receptor 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 [10] receptors and T cell receptors.

Extracellular[edit]
Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane. This binding stimulates a series of events inside the cell; different types of receptor stimulate different responses and receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand [23] induces a change in theconformation of the inside part of the receptor. These result in either the activation of an enzyme in the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm. In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples include tyrosine kinase and phosphatases. Some of them createsecond messengers such as cyclic AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with adaptor proteins that facilitate signalling protein interactions and coordination of signalling complexes necessary to respond to a particular stimulus. Enzymes and adaptor proteins are both responsive to various second messenger molecules. Many adaptor proteins and enzymes activated as part of signal transduction possess specialized protein domains that bind to specific secondary messenger molecules. For example, calcium ions bind to the EF hand domains of calmodulin, allowing it to bind and activate calmodulin-dependent kinase. PIP3 and other phosphoinositides do the same thing to the Pleckstrin homology domains of proteins such as the kinase protein AKT.

G protein-coupled[edit]
Main article: G-protein-coupled receptor G protein-coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimeric G protein. Many receptors are in this family, including adrenergic receptors and chemokine receptors. Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; it exists as a heterotrimer consisting of G, G, and G. Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing G to bind a molecule of GTP and dissociate from the other two G-protein subunits. The dissociation [24] exposes sites on the subunits that can interact with other molecules. The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such asphospholipases and ion channels, the latter permitting the release of [25] second messenger molecules. The total strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic enzymatic activity. A study was conducted where a point mutation was inserted into the gene encoding the chemokine receptor CXCR2; mutated cells underwent a malignant transformation due to the expression of CXCR2 in an active conformation despite the absence of chemokine[26] binding. This meant that chemokine receptors can contribute to cancer development.

Intracellular[edit]
Main article: Intracellular receptor Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are lipophilichormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, enabling gene transcription and protein production. Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Due to their enabling gene transcription, they are alternatively called inductors of gene expression. All hormones that act by regulation of gene expression have two consequences in their mechanism of action; their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor. Signal transduction via these receptors involves little proteins, but the details of gene regulation by this method are not well-understood. Nucleic receptors have DNA-binding domains containingzinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for transactivation used for communication with the translational apparatus. Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol; in the absence of steroids, they cling together in an aporeceptor complex containing chaperone orheatshock proteins (HSPs). The HSPs are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden; activity can be enhanced by phosphorylation of serineresidues at their N-terminal as a result of another signal transduction pathway, a process called crosstalk. Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from a precursorlike retinol brought to the cell through the bloodstream or a completely intracellularly synthesised ligand like prostaglandin. These receptors are located in the nucleus and are not accompanied by HSPs; they repress their gene by binding to their specific DNA sequence when no ligand binds to them, and vice versa. Certain intracellular receptors of the immune system are cytoplasmic receptors; recently identified NOD-like receptors (NLRs) reside in the cytoplasm of some eukaryotic cells and interact with ligands using a leucine-rich repeat (LRR) motif similar to TLRs. Some of these molecules like NOD2 interact with RIP2 kinase that activates NF-B signaling, whereas others

like NALP3 interact with inflammatory caspases and initiate processing of [36][37] particular cytokines like interleukin-1.