Receptor

A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific effect in the cell.

1. RECEPTOR

2. RECEPTOR JAI NARAIN VYAS UNIVERSITY, JODHPUR ASSISTANT PROFESSOR:- ASHWIN SINGH CHOUHAN DEPARTMENT:- PHARMACOLOGY E-mail:- [email protected]

3. JNVU PHARMACY, JODHPIUR INTRODUCTION Receptors  are protein molecules inside the target cell or on its surface that receive a chemical signal. Chemical signals are released by signaling cells in the form of small, usually volatile or soluble molecules called  ligands .  A ligand is a molecule that binds another specific molecule, in some cases, delivering a signal in the process. Ligands can thus be thought of as signaling molecules. Ligands and receptors exist in several varieties; however, a specific ligand will have a specific receptor that typically binds only that ligand .

4. Receptors are protein molecules that recognize and respond to the body’s own (endogenous) chemical messengers, such as hormones or neurotransmitters. Drug molecules may combine with receptors to initiate a series of physiological and biochemical changes. Receptor- mediated drug effects involve two distinct processes: binding, which is the formation of the drug-receptor complex, and receptor activation, which moderates the effect. The term affinity describes the tendency of a drug to bind to a receptor; efficacy (sometimes called intrinsic activity) describes the ability of the drug-receptor complex to produce a physiological response. Together, the affinity and the efficacy of a drug determine its potency . JNVU PHARMACY, JODHPIUR

5. Differences in efficacy determine whether a drug that binds to a receptor is classified as an agonist or as an antagonist. A drug whose efficacy and affinity are sufficient for it to be able to bind to a receptor and affect cell function is an agonist. A drug with the affinity to bind to a receptor but without the efficacy to elicit a response is an antagonist. After binding to a receptor, an antagonist can block the effect of an agonist. The degree of binding of a drug to a receptor can be measured directly by the use of radioactively  labeled drugs or inferred indirectly from measurements of the biological effects of agonists and antagonists. Such measurements have shown that the following reaction generally obeys the law of mass action in its simplest form: drug + receptor ⇌ drug-receptor complex. Thus, there is a relationship between the concentration of a drug and the amount of drug-receptor complex formed. JNVU PHARMACY, JODHPIUR

6. Receptor ligands can be distinguished on the basis of their potential to initiate a biological response following receptor binding: Agonists  bind to a receptor protein to produce a conformational change, which is necessary to initiate a signal that is coupled to a biological response. As the free ligand concentration increases, so does the proportion of receptors occupied, and hence the biological effect. When all of the receptors are occupied the maximum biological effect is achieved. It has been observed in many receptor systems that full agonists can elicit the maximum effect without occupying all available receptors, suggesting the concept of ‘spare receptors’. This apparent excess of receptors allows full responses to occur at lower ligand concentrations than would otherwise be required. Antagonists  bind to a receptor but do not produce the conformational change that initiates an intracellular signal. Occupation of the receptor by a competitive antagonist prevents binding of other ligand and so 'antagonizes' the biological response to the agonist. The inhibition that antagonists produce can be overcome by increasing the dose of the agonist. Some antagonists interfere with the response to the agonist in other ways than receptor competition and are known as non-competitive antagonists. Simply increasing the dose of the agonist cannot overcome their effects and so the maximum response to the agonist (its 'efficacy') is reduced . JNVU PHARMACY, JODHPIUR

7. Partial agonists  are able to activate a receptor but cannot produce a maximal signaling effect equivalent to that of a full agonist even when all available receptors are occupied. When mixed with full agonists, partial agonists block receptor sites that could potentially be occupied by the full agonist, which reduces the overall response (i.e. they seem to antagonize the effect of the full agonist). Partial agonists have some advantages as therapeutic agents. Although they are unable to achieve the same maximum effect as the full agonist, they are less likely to produce receptor-mediated adverse effects at the top of their dose–response curve (e.g. the partial opioid receptor agonist buprenorphine does not cause as much respiratory depression as morphine when it is used as an analgesic). Inverse agonists  produce the opposite effect to the full agonist when they bind to a receptor. For inverse agonists to be identified, the relevant endogenous receptor must show some degree of coupling to a biological response even in the absence of ligand binding (i.e. constitutive activity). Many receptors possess constitutive activity. JNVU PHARMACY, JODHPIUR

8. IMPORTANT FUNCTIONS OF RECEPTORS: Globular proteins (receptors) acting as a cell’s ‘letter boxes’. Located mostly in the cell membrane. Receive messages from chemical messengers coming from other cells. Transmit a message into the cell leading to a cellular effect. Different receptors specific for different chemical messengers. Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers. JNVU PHARMACY, JODHPIUR

9. JNVU PHARMACY, JODHPIUR TYPES OF RECEPTORS Receptors come in many types, but they can be divided into two categories: intracellular receptors, which are found inside of the cell (in the cytoplasm or nucleus), and cell surface receptors, which are found in the plasma membrane.

10. Type 1:  Ligand -gated ion channels ( ionotropic receptors ) – These receptors are typically the targets of fast neurotransmitters such as acetylcholine (nicotinic) and GABA; activation of these receptors results in changes in ion movement across a membrane. They have a heteromeric structure in that each subunit consists of the extracellular ligand -binding domain and a transmembrane domain which includes four transmembrane  alpha helices. The ligand -binding cavities are located at the interface between the subunits. Type 2: G protein-coupled receptors ( metabotropic receptors ) – 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 peptide ligands is usually located in the extracellular domain whereas the binding site for smaller non-peptide ligands is often located between the seven alpha helices and one extracellular loop. The aforementioned receptors are coupled to different intracellular effector systems via G proteins . JNVU PHARMACY, JODHPIUR

11. Type 3: Kinase -linked and related receptors (see "Receptor tyrosine kinase " and "Enzyme-linked receptor") – They are composed of an extracellular domain containing the ligand binding site and an intracellular domain, often with enzymatic-function, linked by a single transmembrane alpha helix. The insulin receptor is an example. Type 4: Nuclear receptors  – While they are called nuclear receptors, they are actually located in the cytoplasm 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 recognizing the DNA sequences specific to this receptor. The N terminus 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 receptors are examples of such receptors. JNVU PHARMACY, JODHPIUR

12. JNVU PHARMACY, JODHPIUR Intracellular receptors Intracellular receptors  are receptor proteins found on the inside of the cell, typically in the cytoplasm or nucleus. In most cases, the ligands of intracellular receptors are small, hydrophobic (water-hating) molecules, since they must be able to cross the plasma membrane in order to reach their receptors. For example, the primary receptors for hydrophobic steroid hormones, such as the sex hormones estradiol (an estrogen ) and testosterone, are intracellular^{1,2}1,2start superscript, 1, comma, 2, end superscript. When a hormone enters a cell and binds to its receptor, it causes the receptor to change shape, allowing the receptor-hormone complex to enter the nucleus (if it wasn’t there already) and regulate gene activity. Hormone binding exposes regions of the receptor that have DNA-binding activity, meaning they can attach to specific sequences of DNA. These sequences are found next to certain genes in the DNA of the cell, and when the receptor binds next to these genes, it alters their level of transcription.

13. JNVU PHARMACY, JODHPIUR Many signaling pathways, involving both intracellular and cell surface receptors, cause changes in the transcription of genes. However, intracellular receptors are unique because they cause these changes very directly, binding to the DNA and altering transcription themselves.

14. JNVU PHARMACY, JODHPIUR CELL-SURFACE RECEPTORS Cell-surface receptors  are membrane-anchored proteins that bind to ligands on the outside surface of the cell. In this type of signaling , the ligand does not need to cross the plasma membrane. So, many different kinds of molecules (including large, hydrophilic or "water-loving" ones) may act as ligands . A typical cell-surface receptor has three different  domains , or protein regions: a extracellular ("outside of cell") ligand -binding domain, a hydrophobic domain extending through the membrane, and an intracellular ("inside of cell") domain, which often transmits a signal. The size and structure of these regions can vary a lot depending on the type of receptor, and the hydrophobic region may consist of multiple stretches of amino acids that criss-cross the membrane.

15. JNVU PHARMACY, JODHPIUR This diagram shows a G protein-coupled receptor (GPCR), a type of receptor we'll examine in more detail later in the article. GPCRs have seven membrane-spanning domains, as shown by the seven segments crossing the gray region that represents the plasma membrane. There are many kinds of cell-surface receptors, but here we’ll look at three common types: ligand -gated ion channels, G protein-coupled receptors, and receptor tyrosine kinases .

16. JNVU PHARMACY, JODHPIUR LIGAND-GATED ION CHANNELS Ligand -gated ion channels  are ion channels that can open in response to the binding of a ligand . To form a channel, this type of cell-surface receptor has a membrane-spanning region with a hydrophilic (water-loving) channel through the middle of it. The channel lets ions to cross the membrane without having to touch the hydrophobic core of the  phospholipid bilayer . When a ligand binds to the extracellular region of the channel, the protein’s structure changes in such a way that ions of a particular type, such as \text{Ca}^{2+}Ca2+start text, C, a, end text, start superscript, 2, plus, end superscript or \text{ Cl }^- Cl −start text, C, l, end text, start superscript, minus, end superscript, can pass through. In some cases, the reverse is actually true: the channel is usually open, and ligand binding causes it to close. Changes in ion levels inside the cell can change the activity of other molecules, such as ion-binding enzymes and voltage-sensitive channels, to produce a response. Neurons, or nerve cells, have ligand -gated channels that are bound by neurotransmitters.

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18. JNVU PHARMACY, JODHPIUR G PROTEIN-COUPLED RECEPTORS G protein-coupled receptors  ( GPCRs ) are a large family of cell surface receptors that share a common structure and method of signaling . The members of the GPCR family all have seven different protein segments that cross the membrane, and they transmit signals inside the cell through a type of protein called a G protein (more details below). GPCRs are diverse and bind many different types of ligands . One particularly interesting class of GPCRs is the odorant (scent) receptors. There are about 800800800 of them in humans, and each binds its own “scent molecule” – such as a particular chemical in perfume, or a certain compound released by rotting fish – and causes a signal to be sent to the brain, making us smell a smell!^33cubed When its ligand is not present, a G protein-coupled receptor waits at the plasma membrane in an inactive state. For at least some types of GPCRs, the inactive receptor is already docked to its signaling target, a  G protein ^44start superscript, 4, end superscript. G proteins come in different types, but they all bind the nucleotide guanosine triphosphate (GTP), which they can break down (hydrolyze) to form GDP. A G protein attached to GTP is active, or “on,” while a G protein that’s bound to GDP is inactive, or “off.” The G proteins that associate with GPCRs are a type made up of three subunits, known as  heterotrimeric G proteins . When they’re attached to an inactive receptor, they’re in the “off” form (bound to GDP).

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20. JNVU PHARMACY, JODHPIUR Ligand binding, however, changes the picture: the GPCR is activated and causes the G protein to exchange GDP for GTP. The now-active G protein separates into two pieces (one called the α subunit, the other consisting of the β and γ subunits), which are freed from the GPCR. The subunits can interact with other proteins, triggering a signaling pathway that leads to a response. Eventually, the α subunit will hydrolyze GTP back to GDP, at which point the G protein becomes inactive. The inactive G protein reassembles as a three-piece unit associated with a GPCR. Cell signaling using G protein-coupled receptors is a cycle, one that can repeat over and over in response to ligand binding. G protein-coupled receptors play many different roles in the human body, and disruption of GPCR signaling can cause disease. 

21. JNVU PHARMACY, JODHPIUR RECEPTOR TYROSINE KINASES Enzyme-linked receptors  are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor actually  is  an enzyme that can catalyze a reaction. Other enzyme-linked receptors have an intracellular domain that interacts with an enzyme^55start superscript, 5, end superscript. Receptor tyrosine kinases  ( RTKs ) are a class of enzyme-linked receptors found in humans and many other species. A  kinase  is just a name for an enzyme that transfers phosphate groups to a protein or other target, and a receptor tyrosine kinase transfers phosphate groups specifically to the amino acid tyrosine. How does RTK signaling work? In a typical example, signaling molecules first bind to the extracellular domains of two nearby receptor tyrosine kinases . The two neighboring receptors then come together, or dimerize . The receptors then attach phosphates to tyrosines in each others' intracellular domains. The phosphorylated tyrosine can transmit the signal to other molecules in the cell.

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23. JNVU PHARMACY, JODHPIUR In many cases, the phosphorylated receptors serve as a docking platform for other proteins that contain special types of binding domains. A variety of proteins contain these domains, and when one of these proteins binds, it can initiate a downstream signaling cascade that leads to a cellular response^{6,7}6,7start superscript, 6, comma, 7, end superscript. Receptor tyrosine kinases are crucial to many signaling processes in humans. For instance, they bind to  growth factors , signaling molecules that promote cell division and survival. Growth factors include platelet-derived growth factor (PDGF), which participates in wound healing, and nerve growth factor (NGF), which must be continually supplied to certain types of neurons to keep them alive^88start superscript, 8, end superscript. Because of their role in growth factor signaling , receptor tyrosine kinases are essential in the body, but their activity must be kept in balance: overactive growth factor receptors are associated with some types of cancers.

24. JNVU PHARMACY, JODHPIUR MAIN TYPES OF DRUG TARGETS AND THEIR MECHANISMS OF ACTION DRUG TARGET DESCRIPTION EXAMPLE(S) RECEPTORS CHANNEL-LINKED RECEPTORS Coupled directly to an ion channel. Activation opens the channel, making a cell membrane permeable to specific ions. These channels are known as ‘ ligand -gated’ because it is receptor binding that operates them (in contrast to ‘voltage-gated’ channels that respond to changes in membrane potential. Nicotinic acetylcholine receptors , gamma- Aminobutyric acid (GABA) receptors G-PROTEIN COUPLED RECEPTORS Coupled to intracellular effector mechanisms via a family of closely related 'G‐proteins' that participate in signal transduction by coupling receptor binding to intracellular enzyme activation or the opening of an ion channel. Secondary messenger systems include the enzymes, adenylyl cyclase and guanylyl cyclase , which generate cyclic AMP and cyclic GMP, respectively. Muscarinic acetylcholine receptors ; beta- Adrenoceptors Dopamine receptors ; 5-hydroxytryptamine (Serotonin) receptors ; Opioid receptors KINASE-LINKED RECEPTORS Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions. Insulin receptors NUCLEAR HORMONE RECEPTORS Intracellular and also known as 'nuclear receptors’. Binding of a ligand promotes or inhibits synthesis of new proteins, which may take hours or days to promote a biological effect. Steroid hormone receptors ; Thyroid hormone receptors ; Vitamin D receptors

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