Chapter 11 Cell Communication

Cell Signaling All cells communicate Prokaryotes: first organisms to use signaling Animal cells communicate by: 1. Direct contact (gap junctions) 2. Local regulators (growth factors, neurotransmitters) 3. Long distance (hormones)

Local vs Long Distance Signaling Local regulators – affect only nearby cells Paracrine signaling – cells release chemicals to nearby cells Neurotransmitters released from neurons Direct Contact – between immune cells Long distance- affect distant cells (hormones) Endocrine signaling – chemicals released into blood and carried throughout body How Cells Talk - Need correct receptors - Either inside cell or along cell membrane

Communication by Direct Contact Cells can also pass messages directly Cell Junctions (directly connect cytoplasm of connecting cells Gap junctions ex: cardiac cells- rhythm Plasmodesmata Surface receptors (Cell to Cell recognition) “ID tag” recognition Cell markers Immune responses

Basic Stages of Cell Signaling Signal Transduction Pathway (STP) : steps involved in passing along message to cause cellular effect 1. Reception: Detection of a signal molecule (ligand) coming from outside the cell - causes change in shape of receptor protein Transduction: Convert signal to a form that can bring about a cellular response Response: Cell takes action in response to the signal molecule

Step 1: Reception Chemical signal (ligand) binds to very specific receptor - causes receptor to change shape Types of Receptors Plasma membrane receptor Hydrophilic or large ligands Intracellular receptors (cytoplasm, nucleus) hydrophobic or small ligands ex: testosterone

Step 1: Reception Most signal receptors are proteins on the plasma membrane 4 types: G-Protein Coupled Receptors (GPCP) - most common, over 1000 Tyrosine-Kinase Receptors Ion-Channel Receptors Intracellular Receptors

Reception: Protein Receptors G Protein-Coupled Receptor (GPCR) G-proteins use GTP (not ATP) Functions Embryonic development Sensory reception Hormones and neurotransmitters Involved in human diseases and bacterial infections that produce toxins that interfere with G protein functions ~60% of medicines affect G protein pathways

Reception: Protein Receptors G Protein – Coupled Receptor (GPCR) Signal binds to receptor  G-protein activated  enzyme is activated  cellular response

Reception: Protein Receptors Receptor Tyrosine- Kinase (RTK) Receptors that attach phosphates to tyrosines Have enzyme activity Receptor on membrane, tail in cytoplasm Kinase: catalyzes transfer of phosphates When receptors get signal, they form a “dimer” (two parts come together) Protein (enzyme) pulls PO4 off ATP & adds it to tyrosines on “tail” portion They become activated Message is now relayed to nearby proteins Continues the signaling chain-reaction

Reception: Protein Receptors RTKs (continued) Single ligand binding event triggers many pathways May activate 10+ pathways and cellular responses Coordinates cell growth and reproduction Abnormal RTKs associated with HER 2 breast cancer Too many receptors push cancer cell growth

Reception: Protein Receptors Ion Channel Receptors Ligand Gated Ion Channel Regulates flow of ions thru cell Chemical signal binds to protein channel changing its shape Channel opens/closes Allows/blocks specific ions (Na, Ca) Found in synapses between nerve cells

Reception: Protein Receptors Plasma Membrane Receptors Review G-Protein Coupled Receptor (GPCR) Tyrosine Kinase Ligand-Gated Ion Channels 7 transmembrane segments in membrane Attaches (P) to tyrosine Signal on receptor changes shape G protein + GTP activates enzyme  cell response Activate multiple cellular responses at once Regulate flow of specific ions (Ca2+, Na+)

Intracellular Protein Receptors Some receptors are in cytoplasm or nucleus of target cell (instead of along membrane) Chemical messenger must pass through plasma membrane and activates receptor protein Small or hydrophobic ex: steroids testosterone acts as transcription factor- turns on genes to control male sex characteristics

What determines whether a signal will bind to a membrane protein or an intracellular protein? Membrane signals – cannot get through Large – polar – ionic Intracellular signals – can get through Hydrophobic - small

Which types of cells communicate this way. Most of them Which types of cells communicate this way? Most of them! bacteria – yeast (fungi) – plants - animals

Step 2: Transduction Passing of message - signal molecule not passed along- only message - usually involves changes in the molecules doing the passing due to phosphoryation - relay molecules are proteins - Signal transduction pathway: triggered by reception

Transduction Phosphorylation Cascade Each protein activates next by phosphorylating it Causes cascades of molecular interactions relay signals from receptors  target molecules Last step involves activating protein to cause cellular effect Protein kinase: enzyme that phosphorylates and activates proteins at next level - 1000’s in cells - cascade enhances and amplifies signal Protein phosphatases: enzymes that dephosphorylate (inactivate) proteins - turns of STP

Transduction: Second Messengers Molecules in cytoplasm that receive signal and relay message at accelerated rate (yelling thru window) small, non-protein hydrophilic molecules/ions spread by diffusion initiated by GPCRs and RTKs (1st messengers) faster than hydrophobic messengers- does not require as much signal chemical to produced ex: cyclic AMP (cAMP), calcium ions (Ca2+), inositol triphosphate (IP3)

Transduction: Second Messengers cAMP = cyclic adenosine monophosphate How it works - 1st messenger activates GPCR - G protein adenylyl cyclase S converts ATP to cAMP - cAMP broadcasts signal to cytoplasm - activates protein kinase A leads to cellular response **G proteins can be activators or inhibitors to regulate systems*

Transduction: Second Messengers Calcium Ions and Inositol P3 (IP3) Both used in both G protein and RTK pathways Used in muscle cell contraction, secretion, cell division 3 2 1 IP3 quickly diffuses through the cytosol and binds to an IP3– gated calcium channel in the ER membrane, causing it to open. 4 The calcium ions activate the next protein in one or more signaling pathways. 6 Calcium ions flow out of the ER (down their con- centration gradient), raising the Ca2+ level in the cytosol. 5 DAG functions as a second messenger in other pathways. Phospholipase C cleaves a plasma membrane phospholipid called PIP2 into DAG and IP3. A signal molecule binds to a receptor, leading to activation of phospholipase C. EXTRA- CELLULAR FLUID Signal molecule (first messenger) G protein G-protein-linked receptor Various proteins activated Endoplasmic reticulum (ER) Phospholipase C PIP2 IP3 (second messenger) DAG Cellular response GTP Ca2+ (second messenger) IP3-gated calcium channel

Calcium ions as second messengers affect pathway for heart muscle contraction. - Ca channel blockers as heart medications.

Step 3: Response Cell takes action may occur in cytoplasm or nucleus

Step 3: Response Nuclear Response Signal may trigger products to be made Pathways can regulate genes by activating transcription factors - can turn genes on or off Ex: growth factor signals protein synthesis for proteins needed for growth

Step 3: Response Cytoplasm Response Response may regulate activities Ex: hormone epinephrine signals breakdown of glycogen to glucose Epineprine acts thru GPCR and activates relay molecules (cAMP/RPKs) Activates enzyme to break down glycogen Pathway amplifies hormonal signal and activates many G proteins

Response: Cell Signaling Specificity The type of proteins a cell has determine which signals it responds to and how it responds ex: liver and heart cells will do different things when activated by same hormone, epinepherine liver: increases glycogen breakdown heart: increases heart rate

Response: Scaffolding Proteins Large relay proteins to which other relay proteins are attached Increases efficiency of signal May directly activate other relay proteins

STP Problems/Defects Examples: Diabetes Cholera Autoimmune disease Cancer Neurotoxins, poisons, pesticides Drugs (anesthetics, antihistamines, blood pressure meds)

Termination of the Signal Inactivation mechanisms Signal must be turned off so new signals can be received Binding of signal molecules is reversible activated receptors   inactive receptors Response ceases once concentration of signal molecules drops below a certain threshold, not enough bound on receptor and receptor becomes inactivated

Apoptosis Pre-programmed cell death “cell suicide” damaged, infected, old cells triggered by signals that activate cascade of “suicide” proteins (caspase) Purpose: protects surrounding cells from digestive enzymes Animal development and maintainence may be involved in diseases such as Parkinson’s and Alzheimer’s and some cancers (failure of apoptosis)

Response: Example of apoptosis: Paw development in the mouse

Cell Signaling in Systems: Endocrine Diabetes (insulin- protein hormone) Positive feedback Insulin released in response to rise in blood glucose Insulin binds to insulin receptor Leads to cascade of cellular responsed to increase utpake of glucose into the cells Negative feedback Insulin inhibits production and release of .glucose into the cells

Cell Signaling in Systems: Endocrine Testosterone (lipid hormone)

Cell Signaling In Systems: Immune T-cells (type of WBC) assist other white blood cells in immunologic processes Interluken - 17 (Il-17) : cytokine, helps activate T cells Many new drugs being developing that inhibit this pathway by binding with receptors and reducing production of WBC which cause attack normal body cells and cause inflammation

Cell Signaling In Systems: Nervous Neurotransmitters chemical messengers released into synaptic cleft cause channels to open which passes along the “message”

Cell Signaling: Infections Cholera Disease acquired by drinking contaminated water (w/human feces) Bacteria (Vibrio cholerae) colonizes lining of small intestine and produces toxin Toxin modifies G-protein involved in regulating salt & water secretion G protein stuck in active form  intestinal cells secrete salts, water Infected person develops profuse diarrhea and could die from loss of water and salts