Membrane Transport and Cell Signaling

Membrane Transport and Cell Signaling
5 Membrane Transport and Cell Signaling

Overview: Life at the Edge
Function of plasma membrane: to physically separate the living cell from its surroundings; border; barrier Controls chemical traffic in and out of cell by being selectively permeable, allowing some substances to cross it more easily than others © 2016 Pearson Education, Inc. 2

Concept 5.1: Cellular membranes are fluid mosaics of lipids and proteins
Fluid Mosaic Model for plasma membranes: the membrane is a mosaic of proteins embedded and bobbing in a fluid bilayer of phospholipids. The head groups of PL are hydrophilic and turn outward; while the fatty acid tails are hydrophobic and turn inward. Phospholipids are amphipathic molecules, containing hydrophobic and hydrophilic regions © 2016 Pearson Education, Inc. 3

Fibers of extracellular matrix (ECM) Glyco- protein Glycolipid
Figure 5.2 Fibers of extracellular matrix (ECM) Glyco- protein Glycolipid EXTRA- CELLULAR SIDE OF MEMBRANE Carbohydrate Figure 5.2 Current model of an animal cell’s plasma membrane (cutaway view) Phospholipid Cholesterol Microfilaments of cytoskeleton Peripheral proteins Integral protein CYTOPLASMIC SIDE OF MEMBRANE © 2016 Pearson Education, Inc.

Two phospholipids WATER WATER Hydrophilic head Hydrophobic tail
Figure 5.3 Two phospholipids WATER Hydrophilic head Hydrophobic tail Figure 5.3 Phospholipid bilayer (cross section) WATER © 2016 Pearson Education, Inc.

The Fluidity of Membranes
Most of the lipids and some proteins in a membrane can move laterally As temperatures cool, membranes switch from a fluid state to a solid state To stay fluid, a membrane needs: Phospholipids with unsaturated hydrocarbon tails Cholesterol also maintains fluidity by preventing tight Membranes must be fluid to work properly packing © 2016 Pearson Education, Inc. 6

Unsaturated tails prevent packing.
Figure 5.5 (a) Unsaturated versus saturated hydrocarbon tails. Fluid Viscous Unsaturated tails prevent packing. Saturated tails pack together. (b) Cholesterol reduces membrane fluidity at moderate temperatures, but at low temperatures hinders solidification. Figure 5.5 Factors that affect membrane fluidity Cholesterol © 2016 Pearson Education, Inc.

Membrane Proteins and Their Functions
A membrane is a collage of different proteins embedded in the fluid matrix of the lipid bilayer Proteins determine most of the membrane’s specific functions Integral proteins penetrate the hydrophobic interior of the lipid bilayer Integral proteins that span the membrane are called transmembrane proteins Peripheral proteins are loosely bound to the surface of the membrane © 2016 Pearson Education, Inc. 8

N-terminus EXTRACELLULAR SIDE a helix CYTOPLASMIC SIDE C-terminus
Figure 5.6 N-terminus EXTRACELLULAR SIDE Figure 5.6 The structure of a transmembrane protein a helix CYTOPLASMIC SIDE C-terminus © 2016 Pearson Education, Inc.

6 major functions of membrane proteins
Transport Enzymatic activity Signal transduction Cell-cell recognition Intercellular joining Attachment to the cytoskeleton and extracellular matrix (ECM) NOTE: changed to match altered order in figure 5.7 © 2016 Pearson Education, Inc. 10

ATP Glyco- protein Signaling molecule Receptor Enzymes
Figure 5.7 Signaling molecule Receptor Enzymes ATP Signal transduction (a) Transport (b) Enzymatic activity (c) Signal transduction Figure 5.7 Some functions of membrane proteins Glyco- protein (d) Cell-cell recognition (e) Intercellular joining (f) Attachment to the cytoskeleton and extracellular matrix (ECM) © 2016 Pearson Education, Inc.

The Role of Membrane Carbohydrates in Cell-Cell Recognition
Cells recognize each other by binding to surface molecules on the extracellular surface of the plasma membrane Often contains carbohydrates Golgi body attaches carbohydrates to lipids made by SER and proteins made by RER; forming glycolipids and glycoproteins These become as individual as fingerprints; called cell surface markers © 2016 Pearson Education, Inc. 12

Concept 5.2: Membrane structure results in selective permeability
A cell must regulate transport of substances across cellular boundaries Plasma membranes are selectively permeable, regulating the cell’s molecular traffic © 2016 Pearson Education, Inc. 13

Things That Cross the Membrane Easily:
Cross by diffusion Nonpolar (hydrophobic) molecules Eg hydrocarbons; O2 Can dissolve in the lipid bilayer of the membrane and cross it easily Small polar molecules pass between the PL E.g. H2O; CO2 © 2016 Pearson Education, Inc. 14

Things That Have Difficulty Crossing the Membrane
Large polar (hydrophilic) molecules E.g. glucose All ions Both of these need specific transport proteins Some transport proteins, called channel proteins, have a hydrophilic channel that certain molecules or ions can use as a tunnel Channel proteins called aquaporins facilitate the passage of water NOTE: A transport protein is specific for the substance it moves © 2016 Pearson Education, Inc. 15

Concept 5.3: Passive transport is diffusion of a substance across a membrane with no energy investment Diffusion: The tendency for molecules to spread out evenly into the available space Spontaneous, net movement from a higher concentration DOWN its concentration gradient To equilibrate Passive process, G; needs no energy input (random) Molecules like nonpolars (O2, H2, HC) and small polars (H2O and CO2) diffuse © 2016 Pearson Education, Inc. 16

Membrane (cross section)
Figure 5.9 Molecules of dye Membrane (cross section) WATER Net diffusion Net diffusion Equilibrium (a) Diffusion of one solute Figure 5.9 The diffusion of solutes across a synthetic membrane Net diffusion Net diffusion Equilibrium Net diffusion Net diffusion Equilibrium (b) Diffusion of two solutes © 2016 Pearson Education, Inc.

Osmosis: A Special Type of Diffusion
The diffusion of free water across a selectively permeable membrane Water moves from an area of greater concentration to an area of lesser concentration Spontaneous, passive, needs no energy input, - G Expressed as osmolarity Moles of solute/liter of H2O E.g. the osmolarity of human blood is 300 mosm/L; while seawater is 1,000 mosm/L © 2016 Pearson Education, Inc. 18

Water Balance of Cells Without Walls
Isoosmotic/Isotonic solution: Equal solute concentrations on both sides of membrane Same osmolarity No net movement of water across membrane Hyperosmotic solution: solution with a higher solute concentration compared to inside the cell; cell loses water Hypoosmotic solution: solution with lower colute concentration than inside cell; cell gains water © 2016 Pearson Education, Inc. 19

Hypo Hyper H2O flows from a hypo to a hyper solution Lower
Figure 5.10 Lower concentration of solute (sugar) Higher concentration of solute More similar concentrations of solute Sugar molecule H2O Hypo Hyper Selectively permeable membrane H2O flows from a hypo to a hyper solution Figure 5.10 Osmosis Osmosis © 2016 Pearson Education, Inc.

Water Balance of Animal Cells…no cell walls
Figure 5.11a Water Balance of Animal Cells…no cell walls Hypotonic solution Isotonic solution Hypertonic solution H2O H2O H2O H2O (a) Animal cell Figure 5.11a The water balance of living cells Lysed Normal Shriveled Lyse or burst; water toxicity Normal; our bodies Shrivel or lose water; salty chips; salt on snails © 2016 Pearson Education, Inc.

Water Balance of Plant Cells; have cell walls
Figure 5.11b Water Balance of Plant Cells; have cell walls Hypoosmotic Hyperosmotic Isoosmotic Plasma membrane Cell wall H2O Plasma membrane H2O H2O H2O (b) Plant cell Figure 5.11b The water balance of living cells Turgid (normal) Flaccid Plasmolyzed © 2016 Pearson Education, Inc.

Water Balance of Cells with Walls
Cell walls help maintain water balance A plant cell in a hypotonic solution swells until the wall opposes uptake; the cell is now turgid (very firm) If a plant cell and its surroundings are isotonic, there is no net movement of water into the cell; the cell becomes flaccid (limp), and the plant may wilt In a hypertonic environment, plant cells lose water; eventually, the membrane pulls away from the wall, a usually lethal effect called plasmolysis © 2016 Pearson Education, Inc. 23

Facilitated Diffusion: Passive Transport Aided by Proteins
In facilitated diffusion, transport proteins speed the passive movement of molecules across the plasma membrane Channel proteins provide corridors that allow a specific molecule or ion to cross the membrane Channel proteins include Aquaporins, for facilitated diffusion of water Ion channels that open or close in response to a stimulus (gated channels) © 2016 Pearson Education, Inc. 24

No net energy input is required
Carrier proteins undergo a subtle change in shape that translocates the solute-binding site across the membrane The shape change may be triggered by binding and release of the transported molecule No net energy input is required © 2016 Pearson Education, Inc. 25

EXTRA- CELLULAR FLUID (a) A channel protein Channel protein Solute
Figure 5.13 EXTRA- CELLULAR FLUID (a) A channel protein Channel protein Solute CYTOPLASM Figure 5.13 Two types of transport proteins that carry out facilitated diffusion Solute Carrier protein (b) A carrier protein © 2016 Pearson Education, Inc.

Concept 5.4: Active transport uses energy to move solutes against their gradients
Facilitated diffusion speeds transport of a solute by providing efficient passage through the membrane but does not alter the direction of transport Some transport proteins, however, can move solutes against their concentration gradients © 2016 Pearson Education, Inc. 27

The Need for Energy in Active Transport
Active transport moves substances against their concentration gradients Active transport requires energy, usually in the form of ATP Active transport allows cells to maintain concentration gradients that differ from their surroundings The sodium-potassium pump is one type of active transport system © 2016 Pearson Education, Inc. 28

EXTRA- [Na+] high CELLULAR FLUID [K+] low Na+ Na+ Na+ Na+ Na+ ATP
Figure 5.14 EXTRA- CELLULAR FLUID [Na+] high [K+] low Na+ Na+ Na+ Na+ Na+ CYTO- PLASM [Na+] low ATP Na+ P [K+] high ADP K+ K+ Na+ Na+ Na+ Figure 5.14 The sodium-potassium pump: a specific case of active transport K+ K+ P K+ K+ P P i © 2016 Pearson Education, Inc.

Facilitated diffusion ATP
Figure 5.15 Passive transport Active transport Figure 5.15 Review: passive and active transport Diffusion Facilitated diffusion ATP © 2016 Pearson Education, Inc.

How Ion Pumps Maintain Membrane Potential
Membrane potential is the voltage across a membrane Voltage is created by differences in the distribution of positive and negative ions across a membrane Two combined forces, collectively called the electrochemical gradient, drive the diffusion of ions across a membrane A chemical force (the ion’s concentration gradient) An electrical force (the effect of the membrane potential on the ion’s movement) © 2016 Pearson Education, Inc. 31

An electrogenic pump is a transport protein that generates voltage across a membrane
The sodium-potassium pump is the major electrogenic pump of animal cells The main electrogenic pump of plants, fungi, and bacteria is a proton pump Electrogenic pumps help store energy that can be used for cellular work © 2016 Pearson Education, Inc. 32

ATP EXTRACELLULAR FLUID H+ H+ H+ Proton pump H+ H+ H+ CYTOPLASM
Figure 5.16 ATP EXTRACELLULAR FLUID H+ H+ H+ Proton pump H+ H+ Figure 5.16 A proton pump H+ CYTOPLASM © 2016 Pearson Education, Inc.

Cotransport: Coupled Transport by a Membrane Protein
Cotransport occurs when active transport of a solute indirectly drives transport of other solutes Plant cells use the gradient of hydrogen ions generated by proton pumps to drive active transport of nutrients into the cell © 2016 Pearson Education, Inc. 34

Sucrose Sucrose Sucrose-H+ cotransporter Diffusion of H+ H+ H+ H+ H+
Figure 5.17 +  Sucrose Sucrose Sucrose-H+ cotransporter Diffusion of H+ H+ + H+  H+ + H+  H+ Figure 5.17 Cotransport: active transport driven by a concentration gradient H+ H+ Proton pump H+ ATP  + H+ © 2016 Pearson Education, Inc.

Concept 5.5: Bulk transport across the plasma membrane occurs by exocytosis and endocytosis
Water and small solutes enter or leave the cell through the lipid bilayer or by means of transport proteins Large molecules, such as polysaccharides and proteins, cross the membrane in bulk by means of vesicles Bulk transport requires energy In exocytosis, transport vesicles migrate to the membrane, fuse with it, and release their contents Many secretory cells use exocytosis to export products © 2016 Pearson Education, Inc. 36

Endocytosis In endocytosis, the cell takes in molecules and particulate matter by forming new vesicles from the plasma membrane Endocytosis is a reversal of exocytosis, involving different proteins There are 3 types of endocytosis Phagocytosis (“cellular eating”) Pinocytosis (“cellular drinking”) Receptor-mediated endocytosis © 2016 Pearson Education, Inc. 37

Phagocytosis Pinocytosis Receptor-Mediated Endocytosis EXTRACELLULAR
Figure 5.18 Phagocytosis Pinocytosis Receptor-Mediated Endocytosis EXTRACELLULAR FLUID Solutes Pseudopodium Plasma membrane Receptor Coat protein Food or other particle Coated pit Figure 5.18 Exploring endocytosis in animal cells Coated vesicle Food vacuole CYTOPLASM © 2016 Pearson Education, Inc.

Pseudopodium of amoeba
Figure 5 mm Green algal cell Figure Exploring endocytosis in animal cells (part 4: phagocytosis TEM) Pseudopodium of amoeba An amoeba engulfing a green algal cell via phagocytosis (TEM) © 2016 Pearson Education, Inc.

Pinocytotic vesicles forming (TEMs)
Figure Figure Exploring endocytosis in animal cells (part 5: pinocytosis TEMs) 0.25 mm Pinocytotic vesicles forming (TEMs) © 2016 Pearson Education, Inc.

Bottom: A coated vesicle forming during receptor-mediated
Figure Plasma membrane Coat protein 0.25 mm Figure Exploring endocytosis in animal cells (part 6: receptor-mediated endocytosis TEMs) Top: A coated pit Bottom: A coated vesicle forming during receptor-mediated endocytosis (TEMs) © 2016 Pearson Education, Inc.

Concept 5.6: The plasma membrane plays a key role in most cell signaling
In multicellular organisms, cell-to-cell communication allows the cells of the body to coordinate their activities Communication between cells is also essential for many unicellular organisms 4 essential elements of communication: Signaling cell Signaling molecule Receptor molecule Responding cell © 2016 Pearson Education, Inc. 42

Elements Illustrated 3. 2. 1. 4. These elements are illustrated here:
The signaling cell releases a signaling molecule, which is recognized by the receptor on the receptor cell.

3 Key Steps of Cellular Communication
Figure 5.20-s3 3 Key Steps of Cellular Communication EXTRA- CELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Response Receptor 1 2 3 Activation Relay molecules Figure 5.20-s3 Overview of cell signaling (step 3) Signaling molecule © 2016 Pearson Education, Inc.

Types of Signaling Cell signaling can be classified by the distance between the signaling and responding cells. Synaptic Endocrine Paracrine Autocrine Juxtacrine

Electrical signal triggers release of neurotransmitter.
Figure Local signaling Electrical signal triggers release of neurotransmitter. Neurotransmitter diffuses across synapse. Figure Local and long-distance cell signaling by secreted molecules in animals (part 2: local signaling, synaptic) Target cell (b) Synaptic signaling © 2016 Pearson Education, Inc.

Endocrine Signaling Hormone
Takes place over long distances and relies on the circulatory system for delivery of signaling molecules (I.e. blood glucose; calcium homeostasis) Hormone Some signaling molecules may need to travel great distances in the body through the circulatory system. Signaling by means of molecules traveling through the bloodstream is called endocrine signaling. Examples of endocrine signaling molecules are estrogen and testosterone. These hormones must travel from the ovaries or testes through the bloodstream to target cells in various tissues.

PARACRINE SIGNALING Called local signaling
Cells secrete signaling molecules into extracellular fluid, NOT bloodstream, to signal nearby cells only i.e. inflammation signaling; some differentiation signaling; platelet derived growth factors (PDGF) Paracrine signaling involves two cells that are close to each other. Here, the signaling molecule needs to travel a short distance in order to bind to the neighboring cell’s receptor. These signaling molecules travel distances of up to 20 cell diameters, or a few hundred micrometers. Autocrine signaling is when the signaling cell and the responding cell are one and the same, like we saw earlier with the pneumococcus. Paracrine and autocrine signaling are especially important to multicellular organisms during embryonic development. Takes place over short distances between neighboring cells. Important during embryonic development

Growth factors are small soluble molecules present during paracrine signaling. In paracrine signaling, the signal is usually a small, soluble molecule. Some paracrine signal molecules are known as growth factors because they stimulate cells to grow and divide. In 1974, Nancy Kohler and Allan Lipton discovered [identified the first growth factor. It had long been known] that cultured cells could be maintained in culture in the presence of blood serum [due to unidentified factors present in the serum. Kohler and Lipton were able to determine] and later determined that it was the platelets in the blood serum that secreted these growth factors. In their first experiments, they grew some fibroblasts from [mice] chickens in the presence of plasma and others in the presence of serum. The results [confirmed earlier observations and] showed that those cultured in serum grew at a much higher rate. In other experiments, they wanted to determine if the factor causing the growth was directly released from platelets, so they grew cells in the presence of plasma and cells in the presence of a solution of platelet proteins, and those cells that were exposed to platelet proteins grew at a much higher rate. They later purified this growth factor from the platelets, and we know it today as PDGF (platelet derived growth factor). Growth Factors Some paracrine signals are known as growth factors because they stimulate cells to grow/divide 49

Autocrine Signaling Occurs when a cell signals itself
I.e. blood platelets secrete eicosanoids to influence their own activity; Important during embryonic development

Juxtacrine Signaling Depends on physical contact between cells;
Usually through direct contact of transmembrane proteins I.e. during development of CNS in vertebrates (Delta proteins becomes neurons/Notch proteins become glial cells) Some signaling occurs in the absence of a signaling molecule. Instead, it occurs because of direct contact between neighboring cells. This communication is contact-dependent, or juxtacrine signaling. Here, a transmembrane protein on the surface of one cell acts as the signaling molecule and a transmembrane protein on an adjacent cell acts as the receptor. One example of juxtacrine signaling occurs during the development of the central nervous system in vertebrates. In the developing embryo, some undifferentiated cells begin to express a protein called Delta on their surface. This signal is received by all the cells directly touching the Delta-expressing cell, through a surface protein called Notch. As a result, the Notch expressing cells become supporting glial cells and not neurons. The Delta-expressing cell develops into a neuron.

Signaling Molecule and Receptors
Signaling molecules bind to and activate specific cell-surface and intracellular receptors. Ligand: a signaling molecule Ligand-binding site: location on the receptor to which the ligand binds Binding causes the receptor to undergo a conformational change that activates the receptor The binding of the ligand to the ligand-binding site is very similar to the substrate/active site binding in enzymes. [When a ligand binds to the ligand binding site on its receptor,] The receptor is activated when the ligand binds appropriately because a conformational change in the receptor takes place [that triggers] , signaling the chemical reactions to take place in the cytosol.

Receptor Behavior When ligand bound to receptor
[Most receptors exist in only two alternative states, on or off, like a light switch.] Receptors on the surface of a cell or in the cytosol of a cell act like a light switch. When the ligand is bound, the switch is on, but when it is not bound, the switch is off. When ligand bound to receptor

Cell-Surface Receptors
Receptors for polar signaling molecules (including growth factors) are on the PM Signaling molecules that are polar and cannot pass through the hydrophobic interior of the plasma membrane generally need receptors on the exterior of the cell, or the cell’s surface. When a signaling molecule binds to the ligand-binding site, the entire receptor molecule undergoes a conformational change, activating the receptor.

Three Types of Cell-Surface Receptors
Most water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane 3 major types of cell-surface receptors: G protein-coupled receptors (GPCR) Receptor kinases Ligand-gated ion channels All act as molecular switches There are thousands of different receptor proteins on the surface of any given cell. Most of them can be placed into one of three groups, according to the way they are activated.

Inactive Signaling enzyme Activated molecule GPCR Plasma membrane
Figure 5.21-s2 Inactive enzyme Signaling molecule Activated GPCR GTP Plasma membrane Activated G protein CYTOPLASM Activated enzyme Figure 5.21-s2 A G protein-coupled receptor (GPCR) in action (step 2) GTP Cellular response © 2016 Pearson Education, Inc.

Small Molecules and Ions as Second Messengers
The extracellular signal molecule (ligand) that binds to the receptor is a pathway’s “first messenger” Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion Cyclic AMP and calcium ions are common second messengers © 2016 Pearson Education, Inc. 57

Cyclic AMP (cAMP) is one of the most widely used second messengers
Adenylyl cyclase, an enzyme in the plasma membrane, rapidly converts ATP to cAMP in response to a number of extracellular signals The immediate effect of cAMP is usually the activation of protein kinase A, which then phosphorylates a variety of other proteins © 2016 Pearson Education, Inc. 58

Adenylyl cyclase ATP First messenger (signaling molecule
Figure 5.25 First messenger (signaling molecule such as epinephrine) Adenylyl cyclase G protein GTP G protein-coupled receptor ATP Second messenger cAMP Figure 5.25 cAMP as a second messenger in a G protein signaling pathway Protein kinase A Cellular responses © 2016 Pearson Education, Inc.

Example of G Protein Activation
Adrenaline signaling in heart muscle occurs due to G protein activation Adrenaline signaling in heart muscle occurs due to G protein activation. When adrenaline binds to a G protein-coupled receptor on cardiac muscle cells, GDP in the G protein is replaced by GTP and activates the G protein. The GTP-bound α subunit of the activated G protein then binds to and activates an enzyme in the cell membrane called adenylyl cyclase. This enzyme converts the nucleotide ATP into cyclic AMP. The small signaling molecule cAMP is the second messenger in this system. It binds to and activates another enzyme, a kinase (protein kinase A). The phosphorylation of proteins by protein kinase A cause the rate of contraction to increase. As long as adrenaline is bound to the receptor, the heart rate will remain high. Adrenaline binds to Gprotein receptor, leading to production of 2nd messenger, cAMP, activation of protein kinase A, and increased heart rate.

Termination of G-protein Signal
Termination of the signal depends on the binding affinity of receptor for ligand. The amount of time a signaling molecule remains bound to its receptor depends on how tightly the receptor holds on to it, its binding affinity for the signaling molecule. Once adrenaline leaves the receptor, [the receptor] reverts to its inactive conformation and no longer activates adjacent G proteins. If there is still a high concentration of adrenaline present, another molecule will enter the receptor site and the process repeats. When the concentration of adrenaline returns to normal, the receptors are no longer occupied and they become inactive. Termination of the signal is propagated through the signaling cascade: *G proteins convert GTP to GDP, becoming inactive, which in turn inactivates adenylyl cyclase *enzymes in the cytosol degrade cAMP, which stops the activation of more protein kinase A molecules * phosphatases remove phosphate groups from activated proteins, making them inactive.

Protein Phosphorylation and Dephosphorylation
Phosphorylation and dephosphorylation are a widespread cellular mechanism for regulating protein activity Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation A signaling pathway involving phosphorylation and dephosphorylation can be referred to as a phosphorylation cascade The addition of phosphate groups often changes the form of a protein from inactive to active © 2016 Pearson Education, Inc. 62

Receptor Kinase Active by phosphorylation
Inactive by dephosphorylation A kinase is an enzyme that adds a phosphate group to another molecule in a process called phosphorylation. Phosphatases have the opposite effect and remove a phosphate group. When a protein is phosphorylated by a kinase, it is active and is switched on. [When ligand binds the ligand binding site, receptor kinases become active, phosphorylating other proteins and transmitting the signal from outside the cell to inside the cell.]

Receptor Kinases Receptor kinase signaling:
Limb bud formation to arms/legs Insulin signaling Wound healing (PDGF signals mitosis at wound site Receptor kinase signaling is used in: the formation and elongation of structures called limb buds that become our arms and legs insulin signaling, allowing us to transport glucose across the plasma membrane into the cytosol wound healing—when we cut ourselves, platelet derived growth factor released from platelets in the blood signals to cells at the wound site, triggering cell division to repair the damage A receptor kinase Kit, responsible for the production of pigment in skin, feathers, scales and hair can be seen mutated in these examples. Mutation in a receptor kinase called kit (responsible for pigmentation in skin, feathers, scales, hair)

Ligand-Gated Ion Channel
Neurons with neurons and muscle cells During signaling via ligand-gated ion channels, the binding of a signaling molecule results in the opening of channels in the plasma membrane. During muscle contraction, a neuron sends a signal to a muscle cell, causing it to contract. The signaling molecule released by the neuron is acetylcholine. When acetylcholine receptors are bound to acetylcholine, a conformational change takes place, opening the channel and allowing sodium ions to rush into the muscle cell. This influx of sodium ions changes the membrane potential and contractile machinery of the muscle cell is activated. Movement of ions across the membrane leading to a change in membrane potential

Ligand-gated ion channels: very important in the nervous system
Figure 5.22-s3 Ligand-gated ion channels: very important in the nervous system Gate open Gate closed Ions Signaling molecule (ligand) Cellular response Plasma membrane Ligand-gated ion channel receptor When a ligand binds to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor A ligand-gated ion channel receptor acts as a “gate” for ions when the receptor changes shape Gate closed Figure 5.22-s3 Ion channel receptor (step 3) © 2016 Pearson Education, Inc.

Intracellular Receptors
Intracellular receptor proteins are found in the cytosol or nucleus of target cells These would be activated by small or hydrophobic ligands Ex: steroid and thyroid hormones of animals Nitric oxide (NO) in both plants and animals © 2016 Pearson Education, Inc. 67

Intracellular Receptors
Receptors for nonpolar signaling molecules (such as steroid hormones) are located in the cytosol or in the nucleus Nonpolar signaling molecules that can pass through the hydrophobic core of the plasma membrane don’t need a receptor on the exterior side of the cell. Instead, once the signaling molecule (such as a steroid) is inside the cell, it can bind to receptor proteins located in the cytosol or in the nucleus and form [steroid-receptor] complexes. [Active steroid-receptor complexes often act as transcriptional regulators to control gene expression.]

Receptors Intracellular
Figure 5.23 Intracellular Hormone (aldosterone) Receptors EXTRA- CELLULAR FLUID Hormone secreted by cells of the adrenal gland; Enters cells all over the body, but only kidney cells contain receptors for aldosterone Plasma membrane Receptor protein Hormone- receptor complex Activates genes that control water and sodium flow in kidneys Figure 5.23 Steroid hormone interacting with an intracellular receptor DNA mRNA New protein NUCLEUS CYTOPLASM © 2016 Pearson Education, Inc.

Amplification of Adrenaline Signal
[Signaling through G protein-coupled receptors is amplified at several places, so that a small amount of signal can produce a large response in the cell.] In this example of our body’s response to adrenaline, the adrenaline signal was amplified in three places: [Each adrenaline-bound receptor activates] multiple G proteins activated in the presence of adrenaline [Each] adenylyl cyclase [molecule] produces large amounts of cAMP (second messenger) [Each active] Protein kinase A activates [multiple protein targets] phosphorylation Second messengers like cAMP amplify/activate multiple downstream proteins; therefore, a small amount of signal can cause a large response in the cell.

Growth factor Receptor CYTOPLASM DNA Gene NUCLEUS mRNA Reception
Figure 5.26 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Figure 5.26 Nuclear response to a signal: the activation of a specific gene by a growth factor Response P DNA Gene NUCLEUS mRNA © 2016 Pearson Education, Inc.

Cell Signaling and Cancer
Increased number of receptors Overproduction/altered signaling molecule Ras or receptor kinase mutations Mutations in Ras protein account for 30% of all human cancers. Some cancers prevent Ras from converting GTP (active form) to GDP (inactive form); causing the protein to always be on. Basically, cancer can be caused by malfunction of any step in signaling process of mitosis. Many cancers arise when something goes wrong with the way a cell responds to a signal that leads to cell division or, in some cases, when a cell behaves as if it has received a signal for cell division when in fact it hasn’t. Problems with cell signaling that can lead to cancer can take place at just about every step in the cell-signaling process. Too many receptors can cause cancer because, while there are low levels of the signaling molecule, the increased number of receptors leads to more binding, and depending on the pathway, can lead to abnormal gene expression and excess cell division. Cells can overproduce the signaling molecule or make an altered form of the signaling molecule which would also lead to more chances of binding and lead to abnormal gene expression. Mutations in the Ras protein account for 30% of all human cancers. Some cancers prevent Ras from converting GTP to GDP, causing the protein to always be on.

APOPTOTIC SIGNALING Situations that might lead to apoptotic (programmed cell death) signaling: When a cell realizes that its DNA is irreparably damaged If a WBC signals a cell that it is cancerous or virally infected If a tissue is slated for death for proper development I.e. webbing between fingers

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