The Cellular Internet Biologists have discovered some universal

The “Cellular Internet” • Biologists have discovered some universal mechanisms of cellular regulation that involve cell-to-cell communication. • External signals are converted into responses within the cell Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Methods used by Cells to Communicate • Cell-Cell communication • Cell Signaling using chemical messengers 1. Local signaling over short distances • Cell-Cell Recognition • Local regulators – Paracrine (growth factors) – Synaptic (neurotransmitters) 2. Long distance signaling • Hormones Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Evolution of Cell Signaling • Yeast cells – Identify their mates by cell signaling 1 Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type. 2 Mating. Binding factor Receptor a Yeast cell, factor Yeast cell, mating type a of the factors to receptors induces changes in the cells that lead to their fusion. a 3 New a/ cell. Figure 11. 2 The nucleus of the fused cell includes all the genes from the a and a cells. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings a/

Cell-Cell Communication • Animal and plant cells – Have cell junctions that directly connect the cytoplasm of adjacent cells Plasma membranes Gap junctions between animal cells Plasmodesmata between plant cells Figure 11. 3 (a) Cell junctions. Both animals and plants have cell junctions that allow molecules to pass readily between adjacent cells without crossing plasma membranes. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Cell-Cell Communication § Animal cells use gap junctions to send signals Cells must be in direct contact u Protein channels connecting two adjoining cells u Gap junctions between animal cells AP Biology

Cell-Cell Communication § Plant cells use plasmodesmata to send signals Cells must be in direct contact u Gaps in the cell wall connecting the two adjoining cells together u Plasmodesmata between plant cells AP Biology

Local Signaling: Cell-Cell Recognition • In local signaling, animal cells may communicate via direct contact • Membrane bound cell surface molecules • Glycoproteins • Glyolipids Figure 11. 3(b) Cell-cell recognition. Two cells in an animal may communicate by interaction between molecules protruding from their surfaces. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Local Signaling: Local Regulators • In other cases, animal cells – Communicate using local regulators – Only work over a short distance Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter Neurotransmitter diffuses across synapse Secretory vesicle Local regulator diffuses through extracellular fluid (a) Paracrine signaling. A secreting cell acts on nearby target cells by discharging molecules of a local regulator (a growth factor, for example) into the extracellular fluid. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Target cell is stimulated (b) Synaptic signaling. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell.

Long-distance Signaling: Hormones • In long-distance signaling – Both plants and animals use hormones Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream to target cells Target cell Figure 11. 4 (c) Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all C body cells. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Long-Distance Signaling § Nervous System in Animals u Electrical signals through neurons § Endocrine System in Animals u Uses hormones to transmit messages over long distances § Plants also use hormones Some transported through vascular system u Others are released into the air u AP Biology

The Three Stages of Cell Signaling • Earl W. Sutherland (1971) – Discovered how the hormone epinephrine acts on cells • Sutherland suggested that cells receiving signals went through three processes – Reception – Transduction – Response • Called Signal transduction pathways – Convert signals on a cell’s surface into cellular responses – Are similar in microbes and mammals, suggesting an early origin Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Overview of cell signaling EXTRACELLULAR FLUID 1 Reception CYTOPLASM Plasma membrane 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signal molecule Figure 11. 5 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Three Stages of Cell Signaling EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception Receptor The receptor and signaling molecules fit together (lock and key model, induced fit model, just like enzymes!) Signaling molecule § Signaling molecule binds to the receptor protein AP Biology

Three Stages of Cell Signaling CYTOPLASM EXTRACELLULAR FLUID Plasma membrane 1 Reception 2 Transduction Receptor 2 nd Messenger! Relay molecules in a signal transduction pathway Signaling molecule § The signal is converted into a form that can produce a cellular response AP Biology

Three Stages of Cell Signaling CYTOPLASM EXTRACELLULAR FLUID Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signaling molecule Can be catalysis, activation of a gene, triggering apoptosis, almost anything! § The transduced signal triggers a cellular response AP Biology

Signal Transduction Animation § http: //media. pearsoncmg. com/bc/bc_ campbell_biology_7/media/interactiv emedia/activities/load. html? 11&A § http: //www. wiley. com/legacy/college/bo yer/0470003790/animations/signal_tran sduction/signal_transduction. htm AP Biology

There are three most common types of membrane receptor proteins. § G-protein coupled receptors § Receptor tyrosine-kinases § Ion channel receptors AP Biology

What are the different ways that signals can be passed between cells? § Autocrine § Juxtacrine § Paracrine § Endocrine § https: //www. dnalc. org/resources/3 d/cell signals. html AP Biology

1. Reception • A signal molecule, a ligand, binds to a receptor protein in a lock and key fashion, causing the receptor to change shape. Most receptor proteins are in the cell membrane but some are inside the cell. The G-protein is a common membrane receptor. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

G-Protein Coupled Receptors are often involved in diseases such as bacterial infections. G-Protein Receptors Plasma membrane G protein-coupled receptor Activated receptor Signaling molecule Inactive enzyme Enzyme GDP 1 CYTOPLASM 2 G protein (inactive) GDP GTP Activated enzyme i GTP GDP P 4 3 Cellular response Biology § APhttps: //www. youtube. com/watch? v=V_0 Ec. Ur_txk

Tyrosine Kinase model video • Receptor tyrosine kinases normal and wrong cancer and tk Signal-binding site Signal molecule Helix in the Membrane Tyrosines Tyr CYTOPLASM Tyr Tyr Tyr Tyr Receptor tyrosine kinase proteins (inactive monomers) Tyr Dimer Activated relay proteins Tyr P Tyr Tyr P Tyr Tyr 6 ATP 6 ADP Activated tyrosinekinase regions (unphosphorylated dimer) Fully activated receptor tyrosine-kinase (phosphorylated dimer) Figure 11. 7 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings P Tyr P Tyr P Inactive relay proteins Cellular response 1 Cellular response 2

Ion Channel Receptors § Very important in 1 Gate closed Ions Signaling molecule (ligand) § the nervous system Signal triggers the opening of an ion channel depolarization u Triggered by neurotransmitters Ligand-gated ion channel receptor 2 Gate open u AP Biology Plasma membrane Cellular response 3 Gate closed

2. Transduction • Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell • Multistep pathways – Can amplify a signal (Amplifies the signal by activating multiple copies of the next component in the pathway) – Provide more opportunities for coordination and regulation • At each step in a pathway, the signal is transduced into a different form, commonly a conformational change in a protein. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Fig. 11 -9 Signaling molecule Receptor Transduction: Activated relay molecule Inactive protein kinase 1 A Phosphorylation Cascade Inactive protein kinase 2 ry ho sp o Ph Active protein kinase 1 de ca Inactive protein kinase 3 s ca PP n Pi P Active protein kinase 2 ATP ADP Pi Active protein kinase 3 PP Inactive protein AP Biology tio ADP la ATP P ADP Pi PP Active protein Cellular response

Protein Phosphorylation and Dephosphorylation • Many signal pathways – Include phosphorylation cascades – In this process, a series of protein kinases add a phosphate to the next one in line, activating it – Phosphatase enzymes then remove the phosphates Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

• A phosphorylation cascade Signal molecule Receptor Activated relay molecule Inactive protein kinase 1 1 A relay molecule activates protein kinase 1. Enzymes called protein 5 phosphatases (PP) catalyze the removal of the phosphate groups from the proteins, making them inactive and available for reuse. Figure 11. 8 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings ATP Pi ADP Active protein kinase 3 PP Inactive protein P Finally, active protein 4 kinase 3 phosphorylates a protein (pink) that brings about the cell’s response to the signal. ATP ADP P i PP de ca as Inactive protein kinase 3 c on PP ati Pi Active protein kinase 2 3 then catalyzes the phosphorylation (and activation) of protein kinase 3. P Active protein kinase 2 ADP l ory ATP ph os Inactive protein kinase 2 Ph Active protein kinase 1 2 transfers a phosphate from ATP to an inactive molecule of protein kinase 2, thus activating this second kinase. Active protein kinase 1 P Active protein Cellular response

The transduction stage of signaling is often a multistep process that amplifies the signal. About 1% of our genes are thought to code for kinases. AP Biology

Small Molecules and Ions as Second Messengers • Secondary messengers – Are small, nonprotein, water-soluble molecules or ions that act as secondary messengers. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Cyclic AMP http: //media. pearsoncmg. com/bc/bc_campbell_biology_7/media/intera ctivemedia/activities/load. html? 11&C • Many G-proteins trigger the formation of c. AMP, which then acts as a second messenger in cellular pathways. First messenger (signal molecule such as epinephrine) G protein G-protein-linked receptor Adenylyl cyclase GTP ATP c. AMP Protein kinase A Figure 11. 10 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Cellular responses

Cyclic AMP • Cyclic AMP (c. AMP) – Is made from ATP NH 2 N N O O O N N – O P O P O Ch 2 O O O N N O Pyrophosphate P Pi N N Adenylyl cyclase O OH OH ATP NH 2 O CH 2 O OH Cyclic AMP Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Phoshodiesterase O P O N N O HO P O CH 2 O O H 2 O OH OH AMP

Fig. 11 -11 First messenger Adenylyl cyclase G protein-coupled receptor GTP ATP c. AMP Transduction in a G -protein pathway Second messenger Protein kinase A Cellular responses AP Biology

Calcium ions and Inositol Triphosphate (IP 3) • Calcium, when released into the cytosol of a cell acts as a second messenger in many different pathways Calcium is an important EXTRACELLULAR FLUID ATP Plasma membrane Ca 2+ pump Mitochondrion second messenger because cells are able to regulate its concentration in the cytosol Nucleus CYTOSOL Ca 2+ pump ATP Key Ca 2+ pump Endoplasmic reticulum (ER) High [Ca 2+] Low [Ca 2+] Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Other second messengers such as inositol triphosphate and diacylglycerol can trigger an increase in calcium in the cytosol

http: //www. ncbi. nlm. nih. gov/books/NBK 10883/figure/A 247/? report=objecto nly 1 2 A signal molecule binds Phospholipase C cleaves a to a receptor, leading to plasma membrane phospholipid activation of phospholipase C. called PIP 2 into DAG and IP 3. EXTRACELLULAR FLUID 3 DAG functions as a second messenger in other pathways. Signal molecule (first messenger) G protein DAG GTP G-protein-linked receptor Phospholipase C PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) Ca 2+ (second messenger) Figure 11. 12 4 IP 3 quickly diffuses through the cytosol and binds to an IP 3– gated calcium channel in the ER membrane, causing it to open. Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Various proteins activated 5 Calcium ions flow out of the ER (down their concentration gradient), raising the Ca 2+ level in the cytosol. Cellular response 6 The calcium ions activate the next protein in one or more signaling pathways.

Growth factor 3. Response Receptor Reception § Many possible § outcomes This example shows a transcription response Phosphorylation cascade CYTOPLASM Inactive transcription factor Active transcription factor P DNA Gene NUCLEUS AP Biology Transduction m. RNA Response

Signaling molecule § Specificity of the Receptor signal u u The same signal molecule can trigger different responses Many responses can come from one signal! Relay molecules Response 1 Response 2 Response 3 Cell A. Pathway leads Cell B. Pathway branches, to a single response. leading to two responses. AP Biology

http: //www. hhmi. org/biointeractive/signa l-molecules-trigger-transcription-factors § The signal can § also trigger an activator or inhibitor The signal can also trigger multiple receptors and different responses Activation or inhibition Response 4 Response 5 Cell C. Cross-talk occurs Cell D. Different receptor between two pathways. leads to a different response. AP Biology

Response- cell signaling leads to regulation of transcription (turn genes on or off) or cytoplasmic activities. AP Biology

Long-distance Signaling Intracellular signaling includes hormones that are hydrophobic and can cross the cell membrane. Once inside the cell, the hormone attaches to a protein that takes it into the nucleus where transcription can be stimulated. Testosterone acts as a transcription factor. AP Biology

• Steroid hormones – Bind to intracellular receptors Hormone EXTRACELLULAR (testosterone) FLUID 1 The steroid hormone testosterone passes through the plasma membrane. Plasma membrane Receptor protein Hormonereceptor complex 2 Testosterone binds to a receptor protein in the cytoplasm, activating it. The hormone 3 DNA Figure 11. 6 receptor complex enters the nucleus and binds to specific genes. m. RNA The bound protein 4 NUCLEUS stimulates the transcription of the gene into m. RNA. CYTOPLASM Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings New protein The m. RNA is 5 translated into a specific protein.

Signaling Efficiency: Scaffolding Proteins and Signaling Complexes • Scaffolding proteins – Can increase the signal transduction efficiency Signal molecule Plasma membrane Receptor Scaffolding protein Figure 11. 16 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Three different protein kinases

Termination of the Signal • Signal response is terminated quickly – By the reversal of ligand binding Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Any Questions? ? Can You Hear Me Now? AP Biology

Two systems control all physiological processes 1. Nervous System – neurosecretory glands in endocrine tissues secrete hormones. 2. Endocrine System AP Biology

Human Endocrine System AP Biology

Major Vertebrate Endocrine Glands Their Hormones (Hypothalamus–Parathyroid glands) AP Biology

AP Biology

Neurosecretory cells in endocrine organs and tissues secrete hormones. These hormones are excreted AP Biology into the circulatory system.

Stress and the Adrenal Gland AP Biology http: //highered. mcgrawhill. com/olcweb/cgi/pluginpop. cgi? it=swf: : 535: : /site s/dl/free/0072437316/120109/bio 48. swf: : Action%20 of% 20 Epinephrine%20 on%20 a%20 Liver%20 Cell

Figure 45. 4 One chemical signal, different effects AP Biology

http: //bcs. whfreeman. co m/thelifewire/content/ch p 42/4202003. html AP Biology

http: //vcell. ndsu. nodak. edu/animations/regulatedsecre AP Biology tion/movie. htm

Cellular Communication Review Denise Green AP Biology

REVIEW: Signal-transduction pathway § Definition: Signal on a cell’s surface is converted into a specific cellular response § Local signaling (short distance): § √ Paracrine (growth factors) √ Synaptic (neurotransmitters) Long distance: hormones AP Biology

Stages of cell signaling § Sutherland (‘ 71) § Glycogen depolymerization by epinephrine § 3 steps: • Reception: target cell detection • Transduction: single-step or series of changes • Response: triggering of a specific cellular response AP Biology

• G-protein-linked receptors Signal-binding site Segment that interacts with G proteins G-protein-linked Receptor Plasma Membrane Activated Receptor Signal molecule GDP CYTOPLASM G-protein (inactive) Enzyme GDP GTP Activated enzyme GTP GDP P i Figure 11. 7 Cellular response Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Inctivate enzyme

Protein phosphorylation § Protein activity § § AP Biology regulation Adding phosphate from ATP to a protein (activates proteins) Enzyme: protein kinases (1% of all our genes) Example: cell reproduction Reversal enzyme: protein phosphatases

Second messengers § Non-protein signaling § § pathway Example: cyclic AMP (c. AMP) Ex: Glycogen breakdown with epinephrine Enzyme: adenylyl cyclase G-protein-linked receptor in membrane (guanosine di- or triphosphate) AP Biology

Cellular responses to signals § Cytoplasmic activity § § regulation Cell metabolism regulation Nuclear transcription regulation AP Biology

The three stage of cellular signaling: Reception, Transduction, and Response. § http: //media. pearsoncmg. com/bc/bc_campbell_biology_7/media/interactivemedia/activities/load. html? 11&A AP Biology

2010 Free Response Question AP Biology