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9.1C: Types of Receptors - Biology


Receptors, either intracellular or cell-surface, bind to specific ligands, which activate numerous cellular processes.

Learning Objectives

  • Compare internal receptors with cell-surface receptors

Key Points

  • Intracellular receptors are located in the cytoplasm of the cell and are activated by hydrophobic ligand molecules that can pass through the plasma membrane.
  • Cell-surface receptors bind to an external ligand molecule and convert an extracellular signal into an intracellular signal.
  • Three general categories of cell-surface receptors include: ion -channel, G- protein, and enzyme -linked protein receptors.
  • Ion channel -linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through.
  • G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein, which then interacts with either an ion channel or an enzyme in the membrane.
  • Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme.

Key Terms

  • integral protein: a protein molecule (or assembly of proteins) that is permanently attached to the biological membrane
  • transcription: the synthesis of RNA under the direction of DNA

Types of Receptors

Receptors are protein molecules in the target cell or on its surface that bind ligands. There are two types of receptors: internal receptors and cell-surface receptors.

Internal receptors

Internal receptors, also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell’s DNA into a sequence of amino acids that ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, binds to specific regulatory regions of the chromosomal DNA, and promotes the initiation of transcription. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

Cell-Surface Receptors

Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Each cell-surface receptor has three main components: an external ligand-binding domain (extracellular domain), a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The size and extent of each of these domains vary widely, depending on the type of receptor.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion Channel-Linked Receptors

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the protein’s structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through.

G-Protein Linked Receptors

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane. All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a newly-revealed site on the receptor specific for its binding. Once the G-protein binds to the receptor, the resultant shape change activates the G-protein, which releases GDP and picks up GTP. The subunits of the G-protein then split into the α subunit and the β subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. Later, the GTP on the active α subunit of the G-protein is hydrolyzed to GDP and the β subunit is deactivated. The subunits reassociate to form the inactive G-protein, and the cycle starts over.

Enzyme-Linked Receptors

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 itself is an enzyme or the enzyme-linked receptor has an intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane and activates the enzyme, which sets off a chain of events within the cell that eventually leads to a response. An example of this type of enzyme-linked receptor is the tyrosine kinase receptor. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules. Signaling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors, which then dimerize. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors and can then transmit the signal to the next messenger within the cytoplasm.


Structure of the Eye (With Diagram) | Receptors | Biology

In this article we will discuss about the structure of the eye, with the help of suitable diagrams.

The eye is one of the most important of the receptors. It provides us with information on dimensions, colours and the distance of objects in our environment.

How the Eye Produces a Focused Image:

1. Light rays from an object enter the transparent cornea.

2. The cornea ‘bends’ (refracts) the light rays in towards one another.

3. The light rays pass through the aqueous humour and pupil.

4. The transparent, elastic lens is altered in shape.

i. Fatter, to decrease its focal length, or

ii. Thinner, to increase its focal length.

This is called accommodation.

5. The relatively small amount of refraction now produced by the lens brings the rays to focus on the retina.

6. The retina contains light-sensitive cells:

(i) RODS which work well when light intensity is low, and

(ii) CONES which detect colour.

These cells are stimulated by the light of the image, and convert the light energy into electrical energy.

7. Electrical energy, in the form of an impulse, travels along the optic nerve to the brain.

8. The brain de-codes the impulse to produce the sensation of sight.

Other Important Facts:

(i) The image of objects that we are looking directly at (i.e. which are in the centre of our field of vision) falls on a very sensitive part of the retina called the fovea, or yellow spot. This region has far more cones than rods. Cones provide a picture with greater detail and in better colour.

(ii) There are no rods or cones at the point where the retina is joined to the optic nerve. Images formed on this part of the retina are not converted into impulses and relayed to the brain. This region is called the blind spot. We have blind spots in both of our eyes, but are not usually aware of them. Each eye records a different part of our field of view and covers the blind spot of the other.

The ability of the lens to change shape and focus on objects at different distances is called accommodation.

This ability depends on:

(i) The elasticity of the lens

(ii) The existence of ciliary muscles which are used to alter the shape of the lens

(iii) The suspensory ligaments which transfer the effect of the ciliary muscles to the lens.

The Value of having Two Eyes:

Apart from overcoming the effect of the blind spot, two eyes view the same picture from two slightly different positions. This provides vision in three dimensions, the ability to judge distance (and therefore speed), and offers animals a chance of survival even if one eye is damaged.

The ‘Pupil’ (or Iris) Reflex:

Bright light could seriously damage the delicate light-sensitive cells of the retina. The intensity of light falling on the retina is therefore controlled by the iris. It has an antagonistic arrangement of circular and radial muscles.


9.1 Signaling Molecules and Cellular Receptors

By the end of this section, you will be able to do the following:

  • Describe four types of signaling mechanisms found in multicellular organisms
  • Compare internal receptors with cell-surface receptors
  • Recognize the relationship between a ligand’s structure and its mechanism of action

There are two kinds of communication in the world of living cells. Communication between cells is called intercellular signaling , and communication within a cell is called intracellular signaling . An easy way to remember the distinction is by understanding the Latin origin of the prefixes: inter- means "between" (for example, intersecting lines are those that cross each other) and intra- means "inside" (as in intravenous).

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 interact with proteins in target cells , which are cells that are affected by chemical signals these proteins are also called receptors . Ligands and receptors exist in several varieties however, a specific ligand will have a specific receptor that typically binds only that ligand.

Forms of Signaling

There are four categories of chemical signaling found in multicellular organisms: paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions (Figure 9.2). The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. We should note here that not all cells are affected by the same signals.

Paracrine Signaling

Signals that act locally between cells that are close together are called paracrine signals . Paracrine signals move by diffusion through the extracellular matrix. These types of signals usually elicit quick responses that last only a short period of time. In order to keep the response localized, paracrine ligand molecules are normally quickly degraded by enzymes or removed by neighboring cells. Removing the signals will reestablish the concentration gradient for the signal, allowing them to quickly diffuse through the intracellular space if released again.

One example of paracrine signaling is the transfer of signals across synapses between nerve cells. A nerve cell consists of a cell body, several short, branched extensions called dendrites that receive stimuli, and a long extension called an axon, which transmits signals to other nerve cells or muscle cells. The junction between nerve cells where signal transmission occurs is called a synapse. A synaptic signal is a chemical signal that travels between nerve cells. Signals within the nerve cells are propagated by fast-moving electrical impulses. When these impulses reach the end of the axon, the signal continues on to a dendrite of the next cell by the release of chemical ligands called neurotransmitters from the presynaptic cell (the cell emitting the signal). The neurotransmitters are transported across the very small distances (20–40 nanometers) between nerve cells, which are called chemical synapses (Figure 9.3). The small distance between nerve cells allows the signal to travel quickly this enables an immediate response, such as, "Take your hand off the stove!"

When the neurotransmitter binds the receptor on the surface of the postsynaptic cell, the electrochemical potential of the target cell changes, and the next electrical impulse is launched. The neurotransmitters that are released into the chemical synapse are degraded quickly or get reabsorbed by the presynaptic cell so that the recipient nerve cell can recover quickly and be prepared to respond rapidly to the next synaptic signal.

Endocrine Signaling

Signals from distant cells are called endocrine signals , and they originate from endocrine cells . (In the body, many endocrine cells are located in endocrine glands, such as the thyroid gland, the hypothalamus, and the pituitary gland.) These types of signals usually produce a slower response but have a longer-lasting effect. The ligands released in endocrine signaling are called hormones, signaling molecules that are produced in one part of the body but affect other body regions some distance away.

Hormones travel the large distances between endocrine cells and their target cells via the bloodstream, which is a relatively slow way to move throughout the body. Because of their form of transport, hormones become diluted and are present in low concentrations when they act on their target cells. This is different from paracrine signaling, in which local concentrations of ligands can be very high.

Autocrine Signaling

Autocrine signals are produced by signaling cells that can also bind to the ligand that is released. This means the signaling cell and the target cell can be the same or a similar cell (the prefix auto- means self, a reminder that the signaling cell sends a signal to itself). This type of signaling often occurs during the early development of an organism to ensure that cells develop into the correct tissues and take on the proper function. Autocrine signaling also regulates pain sensation and inflammatory responses. Further, if a cell is infected with a virus, the cell can signal itself to undergo programmed cell death, killing the virus in the process. In some cases, neighboring cells of the same type are also influenced by the released ligand. In embryological development, this process of stimulating a group of neighboring cells may help to direct the differentiation of identical cells into the same cell type, thus ensuring the proper developmental outcome.

Direct Signaling Across Gap Junctions

Gap junctions in animals and plasmodesmata in plants are connections between the plasma membranes of neighboring cells. These fluid-filled channels allow small signaling molecules, called intracellular mediators , to diffuse between the two cells. Small molecules or ions, such as calcium ions (Ca 2+ ), are able to move between cells, but large molecules like proteins and DNA cannot fit through the channels. The specificity of the channels ensures that the cells remain independent but can quickly and easily transmit signals. The transfer of signaling molecules communicates the current state of the cell that is directly next to the target cell this allows a group of cells to coordinate their response to a signal that only one of them may have received. In plants, plasmodesmata are ubiquitous, making the entire plant into a giant communication network.

Types of Receptors

Receptors are protein molecules in the target cell or on its surface that bind ligand. There are two types of receptors, internal receptors and cell-surface receptors.

Internal receptors

Internal receptors , also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell's DNA into a sequence of amino acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change is triggered that exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the chromosomal DNA and promotes the initiation of transcription (Figure 9.4). Transcription is the process of copying the information in a cell's DNA into a special form of RNA called messenger RNA (mRNA) the cell uses information in the mRNA (which moves out into the cytoplasm and associates with ribosomes) to link specific amino acids in the correct order, producing a protein. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

Cell-Surface Receptors

Cell-surface receptors , also known as transmembrane receptors, are cell surface, membrane-anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, through which an extracellular signal is converted into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Because cell-surface receptor proteins are fundamental to normal cell functioning, it should come as no surprise that a malfunction in any one of these proteins could have severe consequences. Errors in the protein structures of certain receptor molecules have been shown to play a role in hypertension (high blood pressure), asthma, heart disease, and cancer.

Each cell-surface receptor has three main components: an external ligand-binding domain called the extracellular domain , a hydrophobic membrane-spanning region called a transmembrane domain, and an intracellular domain inside the cell. The size and extent of each of these domains vary widely, depending on the type of receptor.

Evolution Connection

How Viruses Recognize a Host

Unlike living cells, many viruses do not have a plasma membrane or any of the structures necessary to sustain metabolic life. Some viruses are simply composed of an inert protein shell enclosing DNA or RNA. To reproduce, viruses must invade a living cell, which serves as a host, and then take over the hosts cellular apparatus. But how does a virus recognize its host?

Viruses often bind to cell-surface receptors on the host cell. For example, the virus that causes human influenza (flu) binds specifically to receptors on membranes of cells of the respiratory system. Chemical differences in the cell-surface receptors among hosts mean that a virus that infects a specific species (for example, humans) often cannot infect another species (for example, chickens).

However, viruses have very small amounts of DNA or RNA compared to humans, and, as a result, viral reproduction can occur rapidly. Viral reproduction invariably produces errors that can lead to changes in newly produced viruses these changes mean that the viral proteins that interact with cell-surface receptors may evolve in such a way that they can bind to receptors in a new host. Such changes happen randomly and quite often in the reproductive cycle of a virus, but the changes only matter if a virus with new binding properties comes into contact with a suitable host. In the case of influenza, this situation can occur in settings where animals and people are in close contact, such as poultry and swine farms. 1 Once a virus jumps the former "species barrier" to a new host, it can spread quickly. Scientists watch newly appearing viruses (called emerging viruses) closely in the hope that such monitoring can reduce the likelihood of global viral epidemics.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the double layer of phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the protein's structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through (Figure 9.5).

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane (Figure 9.6). All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a newly revealed site on the receptor specific for its binding. Once the G-protein binds to the receptor, the resulting change in shape activates the G-protein, which releases guanosine diphosphate (GDP) and picks up guanosine 3-phosphate (GTP). The subunits of the G-protein then split into the α subunit and the βγ subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. After awhile, the GTP on the active α subunit of the G-protein is hydrolyzed to GDP and the βγ subunit is deactivated. The subunits reassociate to form the inactive G-protein and the cycle begins anew.

G-protein-linked receptors have been extensively studied and much has been learned about their roles in maintaining health. Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis, botulism, and cholera. In cholera (Figure 9.7), for example, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body and potentially fatal dehydration as a result.

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 itself is an enzyme. Other enzyme-linked receptors have a small intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response. One example of this type of enzyme-linked receptor is the tyrosine kinase receptor (Figure 9.8). A kinase is an enzyme that transfers phosphate groups from ATP to another protein. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules (tyrosine residues). First, signaling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors. The two neighboring receptors then bond together, or dimerize. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors (phosphorylation). The phosphorylated residues can then transmit the signal to the next messenger within the cytoplasm.

Visual Connection

HER2 is a receptor tyrosine kinase. In 30 percent of human breast cancers, HER2 is permanently activated, resulting in unregulated cell division. Lapatinib, a drug used to treat breast cancer, inhibits HER2 receptor tyrosine kinase autophosphorylation (the process by which the receptor adds phosphates onto itself), thus reducing tumor growth by 50 percent. Besides autophosphorylation, which of the following steps would be inhibited by Lapatinib?

  1. Signaling molecule binding, dimerization, and the downstream cellular response
  2. Dimerization, and the downstream cellular response
  3. The downstream cellular response
  4. Phosphatase activity, dimerization, and the downsteam cellular response

Signaling Molecules

Produced by signaling cells and the subsequent binding to receptors in target cells, ligands act as chemical signals that travel to the target cells to coordinate responses. The types of molecules that serve as ligands are incredibly varied and range from small proteins to small ions like calcium (Ca 2+ ).

Small Hydrophobic Ligands

Small hydrophobic ligands can directly diffuse through the plasma membrane and interact with internal receptors. Important members of this class of ligands are the steroid hormones. Steroids are lipids that have a hydrocarbon skeleton with four fused rings different steroids have different functional groups attached to the carbon skeleton. Steroid hormones include the female sex hormone, estradiol, which is a type of estrogen the male sex hormone, testosterone and cholesterol, which is an important structural component of biological membranes and a precursor of steriod hormones (Figure 9.9). Other hydrophobic hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic ligands must bind to carrier proteins while they are being transported through the bloodstream.

Water-Soluble Ligands

Water-soluble ligands are polar and, therefore, cannot pass through the plasma membrane unaided sometimes, they are too large to pass through the membrane at all. Instead, most water-soluble ligands bind to the extracellular domain of cell-surface receptors. This group of ligands is quite diverse and includes small molecules, peptides, and proteins.

Other Ligands

Nitric oxide (NO) is a gas that also acts as a ligand. It is able to diffuse directly across the plasma membrane, and one of its roles is to interact with receptors in smooth muscle and induce relaxation of the tissue. NO has a very short half-life and, therefore, only functions over short distances. Nitroglycerin, a treatment for heart disease, acts by triggering the release of NO, which causes blood vessels to dilate (expand), thus restoring blood flow to the heart. NO has become better known recently because the pathway that it affects is targeted by prescription medications for erectile dysfunction, such as Viagra (erection involves dilated blood vessels).


Molecular Mechanisms of Drug Actions

Catherine Litalien , Pierre Beaulieu , in Pediatric Critical Care (Fourth Edition) , 2011

Enzyme-Linked Receptors

Enzyme-linked receptors have an extracellular ligand-binding domain linked to an intracellular domain that possesses an intrinsic catalytic activity. This large and heterogeneous group of membrane receptors can be divided into four subfamilies according to their catalytic activity (tyrosine kinase, guanylate cyclase, tyrosine phosphatase, and serine/threonine kinase). Cytosolic enzymes presenting an activity similar to that of enzyme-linked receptors are also considered to belong to this family of receptors (e.g., soluble guanylate cyclase receptors activated by nitric oxide [NO]).

Tyrosine kinase receptors include receptors for neurotrophin, 16 growth factors (epidermal growth factor [EGF], platelet-derived growth factor [PDGF]), as well as insulin and many other trophic hormones. These receptors shift from an inactive monomeric state to an active dimeric state upon agonist binding (dimerization). This is followed by autophosphorylation of the intracellular domain of each receptor and binding of SH2-domain proteins that are themselves phosphorylated. Depending on the receptor subtype, SH2-domain proteins allow the phosphorylated receptor to activate other functional proteins, which eventually results in stimulation of gene transcription, or are enzymes such as phospholipases, leading to the formation of second messengers (see below). One important pathway involved in the transduction mechanisms of tyrosine kinase receptors include the Ras/Raf/MAP) kinase pathway which is important in cell division, growth, and differentiation ( Figure 117-8 ).

Unlike tyrosine kinase receptors, cytokine receptors do not usually possess intrinsic kinase activity instead, they associate with cytosolic Janus kinases (JAKs). After dimerisation of the receptors that occurs after binding of the cytokine, JAKs phosphorylate tyrosine residues on the receptor, which then result in the binding of another set of proteins called signal transducers and activators of transcription (STATs). The bound STATs are themselves then phosphorylated by the JAKs and dimerize and dissociate to migrate in the nucleus and activate gene expression to regulate diverse biologic processes controlling the synthesis and release of many inflammatory mediators, growth, development, and homeostasis.

Guanylate cyclase–linked receptors are unique because they synthesize their own second messengers upon agonist binding. The natriuretic peptide receptors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) receptors, belong to this family ( Figure 117-9 ). The extracellular NH2-terminal constitutes the binding domain. There is a short transmembrane segment whose role is to anchor the receptor protein to the membrane. The intracellular domain is made of two different entities: (1) a protein kinase homology domain whose function is to control and relay receptor activation to the catalytic domain, and (2) a guanylate cyclase catalytic domain, also known as particulate guanylate cyclase, involved in the synthesis of cyclic guanosine monophosphate (cGMP) from GTP. 17 In addition to this particulate guanylate cyclase (the membrane form of the enzyme), an intracellular soluble form exists. It is a heterodimer consisting of α- and β-subunits, both of which are necessary for enzyme activity, and is expressed in most tissues, though not uniformly. 18 It is activated by intermediate substances derived from the biosynthesis of eicosanoids (prostaglandins and leukotrienes) and by NO and NO donors such as sodium nitroprussate and nitroglycerin (see below). Guanylate cyclases and cGMP-mediated signaling cascades play a central role in the regulation of diverse pathophysiologic processes, including vascular smooth muscle motility, intestinal fluid and electrolyte homeostasis, and retinal phototransduction. 19


Regulated Cell Death Part B

Pascal Schneider , . Cristian R. Smulski , in Methods in Enzymology , 2014

2.4.2 Interactions of tagged receptors with BAFFN-fusion ligands

BAFFN-ligands are cotransfected with EGFP and stained with soluble receptors-Fc ( Fig. 5.1 H) or with an anti-BAFF antibody recognizing the extracellular, membrane-proximal region of BAFF present in all constructs ( Fig. 5.1 A). Transfected human BAFF expresses well at the cell surface. However, other TNF family ligands, for example, mouse BAFF or human TNF, do not, and thus expression as BAFFN-fusion proteins enhances their surface expression ( Bossen et al., 2011 ).

2.4.2.1 Reagents

Soluble receptors-Fc (purified or in Opti-MEM). Rat IgG2a monoclonal antibody anti-BAFF (Buffy1, EnzoLifeSciences). Other reagents are as described in Section 2.4.1.1 .

2.4.2.2 Method

The method is the same as that of Section 2.4.1.2 , with the following modifications:

Cotransfect 293T cells with EGFP and BAFFN-ligand expression plasmids at a 1:7 ratio.

Stain cells with receptors-Fc followed by anti-human PE to detect specific interactions, or with Buffy1 mAb at 40 μg/ml in FACS buffer followed by anti-rat-PE to detect surface expression of the BAFFN-ligand chimer.


4. Endocannabinoid-Mediated Signaling

The basal level of 2-AG is approximately 1000 times higher than AEA in the brain. Through pharmacological manipulations, altered metabolism of 2-AG, but not AEA, exerts remarkable effects in endocannabinoid-mediated retrograde signaling ( Figure 1 ). Given these facts, it is proposed that 2-AG is the primary endogenous ligand for CBRs in the central nervous system (CNS) [32,34,35]. However, AEA has been shown to activate TRPV1, inhibit l -type Ca 2+ channels independently, as well as negatively regulate 2-AG biosynthesis and physiological effects in striatum, underscoring its essential role in the regulation of synaptic transmission [39].

Simplified scheme representing endocannabinoid retrograde signaling mediated synaptic transmission. Endocannabinoids are produced from postsynaptic terminals upon neuronal activation. As the two major endocannabinoids shown in the scheme, 2-arachidonolglycerol (2-AG) is biosynthesized from diacylglycerol (DAG) by diacylglycerol lipase-α (DAGLα), and anandamide (AEA) is synthesized from N-acyl-phosphatidylethanolamine (NAPE) by NAPE-specific phospholipase D (NAPE-PLD). As lipids, endocannabinoids, mainly 2-AG, readily cross the membrane and travel in a retrograde fashion to activate CB1Rs located in the presynaptic terminals. Activated CB1Rs will then inhibit neurotransmitter (NT) release through the suppression of calcium influx. 2-AG is also able to activate CB1Rs located in astrocytes, leading to the release of glutamate. Extra 2-AG in the synaptic cleft is taken up into the presynaptic terminals, via a yet unclear mechanism, and degraded to arachidonic acid (AA) and glycerol by monoacylglycerol lipase (MAGL). On the other hand, AEA, synthesized in postsynaptic terminal, activates intracellular CB1R and other non-CBR targets, such as the transient receptor potential cation channel subfamily V member 1 (TRPV1). Although endocannabinoid retrograde signaling is mainly mediated by 2-AG, AEA can activate presynaptic CB1Rs as well. Fatty acid amide hydrolase (FAAH) is primarily found in postsynaptic terminals and is responsible for degrading AEA to AA and ethanolamine (EtNH2). Although NAPE-PLD is expressed in presynaptic terminals in several brain regions, it is not clear yet whether AEA is responsible for anterograde signaling in the endocannabinoid system. Note that alternative routes exist for the metabolism of endocannabinoids, depending on the brain region and physiological conditions. Thin arrows indicate enzymatic process thick arrows indicate translocation blunted arrow indicates inhibition.

The first conclusive evidence supporting retrograde endocannabinoid signaling came from the observation of depolarization-induced suppression of inhibition (DSI)/excitation (DSE) [9,33,40]. Later, it was discovered that the endocannabinoid system is involved not only in short-term depression, but also in long-term depression (LTD) at both excitatory and inhibitory synapses [9,33]. Since then, the endocannabinoid system has become the most-studied retrograde signaling system in the brain.

In most cases, endocannabinoid-mediated retrograde signaling starts with the production of 2-AG, in response to increased intracellular Ca 2+ concentration and/or activated Gq/11-coupled receptors [9,33,40]. 2-AG is then released into and traverses the extracellular space, via a mechanism not yet fully elucidated, and arrives at the presynaptic terminal where it binds to the CB1R. Activated CB1R suppresses the release of neurotransmitter in two ways: first, by inhibiting voltage-gated Ca 2+ channels, which reduce presynaptic Ca 2+ influx second, by inhibiting adenylyl cyclase (AC) and the subsequent cAMP/PKA pathway, which is involved in LTD [9,33,40]. The termination of signaling requires the degradation of 2-AG by MAGL, which is expressed in selective synaptic terminals and glial cells [9,33,35].

AEA has been shown to contribute to endocannabinoid-mediated synaptic transmission in several ways. AEA is a full agonist of TRPV1, which is purported to participate in endocannabinoid signaling [32]. AEA-mediated LTD (likely via a TRPV1-dependent mechanism) has been reported in several studies [41,42,43,44,45]. The differential recruitment of 2-AG and AEA by various types of presynaptic activity has been described in the extended amygdala [42]. AEA negatively regulates 2-AG metabolism, the effect of which can be mimicked by the activation of TRPV1 [39]. There is also evidence supporting a tonic role of AEA as an endocannabinoid, since chronic blockade of FAAH leads to constant agonism of the endocannabinoid system without reducing CB1R expression, which is opposite to antagonism of MAGL [46].

Endocannabinoids are prominently involved in the suppression of synaptic transmission through multiple mechanisms, independent of synaptic nature or transmission duration [9,33]. CB1R-dependent self-inhibition in postsynaptic neurons has been observed in a subpopulation of neocortical interneurons and pyramidal neurons, as well as in hippocampal CA1 neurons [47,48,49,50]. Accumulated evidence supports endocannabinoid-mediated communication between neurons and microglia [51,52,53]. Previous studies have shown that microglial cells and astrocytes are able to produce their own 2-AG or AEA, although it is not clear yet whether these endocannabinoids are involved in the modulation of synaptic transmission [54].

In contrast, although studies have shown the presence of CB2R in the brain, the role of CB2R in endocannabinoid-mediated synaptic transmission is still largely elusive [55,56,57]. A recent study has reported that in medial prefrontal cortical pyramidal neurons, intracellular CB2R reduces neuronal firing through the opening of Ca 2+ -activated chloride channels, suggesting its involvement in the regulation of neuronal activity [58].


Medical Definition of Receptor

Receptor: 1. In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds a specific substance. There are many receptors. There is a receptor for (insulin there is a receptor for low-density lipoproteins (LDL) etc. To take an example, the receptor for substance P, a molecule that acts as a messenger for the sensation of pain, is a unique harbor on the cell surface where substance P docks. Without this receptor, substance P cannot dock and cannot deliver its message of pain. Variant forms of nuclear hormone receptors mediate processes such as cholesterol metabolism and fatty acid production. Some hormone receptors are implicated in diseases such as diabetes and certain types of cancer. A receptor called PXR appears to jump-start the body's response to unfamiliar chemicals and may be involved in drug-drug interactions.
2. In neurology, a terminal of a sensory nerve that receives and responds to stimuli.


Researchers Discover New Type of Taste Receptor Cells

Most taste cells selectively respond to a specific stimulus type while broadly responsive cells respond to multiple taste qualities. Image credit: Jhanna Flora / Kathryn Medler.

Taste buds in the mouth are critical to our survival and help us to decide whether a food is a good source of nutrients or a potential poison.

They employ three types of taste cells: Type I cells acts as support cells Type II cells detect bitter, sweet and umami tastes and Type III cells detect sour and salty flavors.

To better understand how taste cells detect and signal the presence of different tastes, Dr. Kathryn Medler from the University at Buffalo and colleagues used an engineered mouse model to investigate the signaling pathways that the animals use to relay taste information to the brain.

The researchers discovered a previously unknown subset of Type III cells that were ‘broadly responsive’ and could announce sour stimuli using one signaling pathway, and sweet, bitter and umami stimuli using another.

The idea that mammals might possess broadly responsive taste cells has been put forth by multiple lab groups, but previously, no one had isolated and identified these cells.

The scientists suspect that broadly responsive cells make a significant contribution to our ability to taste.

Their discovery provides new insight into how taste information is sent to the brain for processing, and suggests that taste buds are far more complex than we currently appreciate.

“Taste cells can be either selective or generally responsive to stimuli which is similar to the cells in the brain that process taste information,” Dr. Medler said.

“Future experiments will be focused on understanding how broadly responsive taste cells contribute to taste coding.”

The discovery is reported in a paper in the journal PLoS Genetics.


Connection for AP ® Courses

Just like you communicate with your classmates face-to-face, using your phone, or via e-mail, cells communicate with each other by both inter-and intracellular signaling. Cells detect and respond to changes in the environment using signaling pathways. Signaling pathways enable organisms to coordinate cellular activities and metabolic processes. Errors in these pathways can cause disease. Signaling cells secrete molecules called ligands that bind to target cells and initiate a chain of events within the target cell. For example, when epinephrine is released, binding to target cells, those cells respond by converting glycogen to glucose. Cell communication can happen over short distances. For example, neurotransmitters are released across a synapse to transfer messages between neurons (Figure 1.3). Gap junctions and plasmodesmata allow small molecules, including signaling molecules, to flow between neighboring cells. Cell communication can also happen over long distances using. For example, hormones released from endocrine cells travel to target cells in multiple body systems. How does a ligand such as a hormone traveling through the bloodstream know when it has reached its target organ to initiate a cellular response? Nearly all cell signaling pathways involve three stages: reception, signal transduction, and cellular response.

Cell signaling pathways begin when the ligand binds to a receptor, a protein that is embedded in the plasma membrane of the target cell or found in the cell cytoplasm. The receptors are very specific, and each ligand is recognized by a different one. This stage of the pathway is called reception. Molecules that are nonpolar, such as steroids, diffuse across the cell membrane and bind to internal receptors. In turn, the receptor-ligand complex moves to the nucleus and interacts with cellular DNA. This changes how a gene is expressed. Polar ligands, on the other hand, interact with membrane receptor protein. Some membrane receptors work by changing conformation so that certain ions, such as Na + and K + , can pass through the plasma membrane. Other membrane receptors interact with a G-protein on the cytoplasmic side of the plasma membrane, which causes a series of reactions inside the cell. Disruptions to this process are linked to several diseases, including cholera.

It is important to keep in mind that each cell has a variety of receptors, allowing it to respond to a variety of stimuli. Some receptors can bind several different ligands for example, odorant molecules/receptors associated with the sense of smell in animals. Once the signaling molecule and receptor interact, a cascade of events called signal transduction usually amplifies the signal inside the cell.

The content presented in this section supports the Learning Objectives outlined in Big Idea 3 of the AP ® Biology Curriculum Framework listed. The AP ® Learning Objectives merge Essential knowledge content with one or more of the seven Science Practices. These objectives provide a transparent foundation for the AP ® Biology course, along with inquiry-based laboratory experiences, instructional activities, and AP ® Exam questions.

Big Idea 3 Living systems store, retrieve, transmit, and respond to information essential to life processes.
Enduring Understanding 3.D Cells communicate by generating, transmitting, and receiving chemical signals.
Essential Knowledge 3.D.3 Signal transduction pathways link signal reception with a cellular response.
Science Practice 6.2 The student can construct explanations of phenomena based on evidence produced through scientific practices.
Learning Objective 3.34 The student is able to construct explanations of cell communication through cell-to-cell direct contact or through chemical signaling.
Essential Knowledge 3.D.3 Signal transduction pathways link signal reception with a cellular response.
Science Practice 1.1 The student can create representations and models of natural or man-made phenomena and systems in the domain.
Learning Objective 3.35 The student is able to create representations that depict how cell-to-cell communication occurs by direct contact or from a distance through chemical signaling.

The Science Practices Assessment Ancillary contains additional test questions for this section that will help you prepare for the AP exam. These questions address the following standards:

There are two kinds of communication in the world of living cells. Communication between cells is called intercellular signaling , and communication within a cell is called intracellular signaling . An easy way to remember the distinction is by understanding the Latin origin of the prefixes: inter- means between (for example, intersecting lines are those that cross each other) and intra- means inside (as in intravenous).

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 interact with proteins in target cells , which are cells that are affected by chemical signals these proteins are also called receptors . Ligands and receptors exist in several varieties however, a specific ligand will have a specific receptor that typically binds only that ligand.


The Sense of Touch

The skin contains receptors that enable a person or animal to feel touch. Image by Agustín Ruiz.

The wind howls outside as the rain pounds against the window. With a sudden flash of lightning, the lights in your room go out. Vision won’t help very much in the darkness of the room, but you know there is a flashlight in the nightstand next to the bed. You move your hands toward it, find the drawer handle, and open it. You start to feel around for the flashlight.

As you touch each object in the drawer you can identify it immediately. After a few tries you feel the rubber grooves of the flashlight handle. With a sigh of relief you pull it out of the drawer and turn it on. While you may think you have psychic powers to be able to correctly identify the flashlight from the other items you touched, your skin did most of the work.

Skin has many types of receptors that help you feel the things that you touch. In your body, a receptor is a structure that can get information from the environment. The information is then changed into a signal that can be understood by the nervous system. Receptors that let the body sense touch are located in the top layers of the skin - the dermis and epidermis.

The skin contains different types of receptors. Together, they allow a person to feel sensations like pressure, pain, and temperature. Click for more detail.

Receptors are small in size, but they collect very accurate information when touched. They may sense pain, temperature, pressure, friction, or stretch. Unique receptors respond to each kind of information. This helps provide the body with a full picture of what is touching the skin.

  • Thermoreceptors (thermo = heat) sense temperature. They do this by changing their level of activity. For example, if the temperature becomes colder, thermoreceptors that sense cold will be more active. The ones that sense heat will be less active.
  • Nociceptors (noci = to harm | ceptor = receptor) sense pain, but maybe not pain in the way a person normally thinks about it. We think of different types of pain related to a cut or a burn, but nociceptors can't tell one from the other. They only detect damage to skin cells. So while a person might think about pain as being different for a burn versus a cut, nociceptors get similar information in both cases.
  • Mechanoreceptors (mechano = machine) sense contact with the skin. These receptors are mechanical, which means they feel physical change. The change could be when an object presses firmly or just brushes against the skin.

Touch receptors are neurons. They send information about touch to the brain through action potentials. Image by Nicolas P. Rougher.

While each of these sensory receptors responds to a specific type of touch, they all act in the same way when they are activated. As part of the nervous system, these receptors will fire an action potential. Action potentials are signals sent by the special cells, called neurons, that make up the nervous system. They are used to share many different kinds of information within the nervous system. Action potentials from all of these receptors will send signals to both the spinal cord and the brain.

Neuroscientists still aren't sure how signals from these receptors are changed into information that a person can understand. For example, when you are tickled versus poked, you know right away what happened. But how does the brain let you know whether it's a tickle or a poke based on only a few action potentials? Scientists continue to study this question.