Cell Communication

Cell-to-cell communication External signals are converted into responses within the cell Cells (in multicellular organisms) communicate by a variety of chemical signals. Some examples are: 1. Hormones, such as insulin- Produced in one tissue, travel through bloodstream, interact with certain cells to change cell activity. 2. Neurotransmitters, such as dopamine- Released by one nerve cell (neuron), travels very short distance to adjacent neuron, stimulates nerve cell activity

Signal Transduction Pathways Convert signals on a cell’s surface into cellular responses Are similar in microbes and mammals, suggesting an early origin

Evolution of Cell Signaling Yeast cells (Single Cells) identify their mates by cell signaling  factor Receptor Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type. 1 Mating. Binding of the factors to     receptors induces changes      in the cells that     lead to their     fusion. New a/ cell. The nucleus of the fused cell includes all the genes from the a and a cells. 2 3 Yeast cell, mating type a mating type   a/ a Figure 11.2

Cell Junctions (Animal and Plant cells) Have cell junctions that directly connect the cytoplasm of adjacent cells Plasma membranes Plasmodesmata between plant cells Gap junctions between animal 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.

In local signaling, animal cells may communicate via direct contact Figure 11.3 (b) Cell-cell recognition. Two cells in an animal may communicate by interaction between molecules protruding from their surfaces.

diffuses across synapse Local Regulators In other cases, animal cells communicate using local regulators (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. (b) Synaptic signaling. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell. Local regulator diffuses through extracellular fluid Target cell Secretory vesicle Electrical signal along nerve cell triggers release of neurotransmitter Neurotransmitter diffuses across synapse is stimulated Local signaling Figure 11.4 A B

Long Distance Signaling Both plants and animals use hormones in long distance signaling Hormone travels in bloodstream to target cells (c) Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all body cells. Long-distance signaling Blood vessel Target cell Endocrine cell Figure 11.4 C

Sutherland discovered how the hormone epinephrine acts on cells He suggested that cells receiving signals went through three processes: Reception Transduction Response

Relay molecules in a signal transduction pathway Overview of cell signaling EXTRACELLULAR FLUID Receptor Signal molecule Relay molecules in a signal transduction pathway Plasma membrane CYTOPLASM Activation of cellular response Figure 11.5 Reception 1 Transduction 2 Response 3

Reception Reception- A signal molecule binds to a receptor protein, causing it to change shape The binding between signal molecule (ligand) and receptor is highly specific A conformational change in a receptor is often the initial transduction of the signal Intracellular receptors are cytoplasmic or nuclear proteins Signal molecules that are small or hydrophobic and can readily cross the plasma membrane use these receptors

Receptors in the Plasma Membrane There are three main types of membrane receptors 1. G-protein-linked receptors 2. Tyrosine kinases receptors 3. Ion channel receptors

G-protein-linked receptors Plasma Membrane Enzyme G-protein (inactive) CYTOPLASM Cellular response Activated enzyme Activated Receptor Signal molecule Inctivate Segment that interacts with G proteins GDP GTP P i Signal-binding site Figure 11.7

Tyrosine Kinases Receptor Signal molecule Signal-binding sitea CYTOPLASM Tyrosines Signal molecule Helix in the Membrane Tyr Dimer Receptor tyrosine kinase proteins (inactive monomers) P Cellular response 1 Inactive relay proteins Activated relay proteins Cellular response 2 Activated tyrosine- kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine-kinase (phosphorylated 6 ATP 6 ADP Figure 11.7

Ion Channel Receptors Figure 11.7 Cellular response Gate open Gate close Ligand-gated ion channel receptor Plasma Membrane Signal molecule (ligand) Figure 11.7 Gate closed Ions Ion Channel Receptors

Scaffolding proteins can increase the signal transduction efficiency Signal molecule Receptor Scaffolding protein Three different protein kinases Plasma membrane Figure 11.16

G- Protein linked receptors 3 components- all allosteric proteins that that can change shape in response to signal: 1. Receptor proteins- spans plasma membrane, has receptor site on outside, binding site for G-protein on inside 2. G- protein- loosely attached to inner membrane Acts like on-off switch Inactive form when bound to GDP Active form when bound to GTP G-protein soon breaks GTP down to GDP, so “on” stat switches back to “off” 3. Target- usually a membrane bound enzyme Enzyme is inactive until activated by active G-protein

Examples that use G-proteins: Many hormone receptors Many neurotransmitters Vision and smell in humans Bacterial infections (botulism, cholera, etc.) produce toxins that interfere with G- proteins, leading to disease symptons As many as 60% of all medicines sold today act by influencing G- protein pathways

Bind to intracellular receptors Steroid Hormones Bind to intracellular receptors Hormone (testosterone) EXTRACELLULAR FLUID Receptor protein DNA mRNA NUCLEUS CYTOPLASM Plasma membrane Hormone- receptor complex New protein Figure 11.6 1 The steroid hormone testosterone passes through the plasma membrane. Testosterone binds to a receptor protein in the cytoplasm, activating it. 2 The hormone- receptor complex enters the nucleus and binds to specific genes. 3 The bound protein stimulates the transcription of the gene into mRNA. 4 The mRNA is translated into a specific protein. 5

Signal Transduction Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell 1. Protein Phosphorylation 2. Second Messengers

1. Protein Phosphorylation and Dephosphorylation Multistep pathways Can amplify a signal and provide more opportunities for coordination and regulation At each step in a pathway The signal is transduced into a different form, commonly a conformational/shape change in a protein Include phosphorylation cascades

Protein Phosphorylation In this process A series of protein kinases (enzymes) add a phosphate to the next one in line, activating it Phosphatase enzymes then remove the phosphates Kinases are often linked: Kinase 1 activates kinase 2, which activates kinase 3, etc to final target.

A phosphorylation cascade Signal molecule Active protein kinase 1 2 3 Inactive protein kinase Cellular response Receptor P ATP ADP PP Activated relay molecule i Phosphorylation cascade P  A relay molecule activates protein kinase 1. 1 2 Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of protein kinase 2, thus activating this second kinase. Active protein kinase 2 then catalyzes the phos- phorylation (and activation) of protein kinase 3. 3 Enzymes called protein phosphatases (PP) catalyze the removal of the phosphate groups from the proteins, making them inactive and available for reuse. 5 Finally, active protein kinase 3 phosphorylates a protein (pink) that brings about the cell’s response to the signal. 4 Figure 11.8

2. Second Messengers Second messengers- are small, non-protein, water-soluble molecules or ions Example= cyclic AMP (cAMP) cAMP is made from ATP by enzyme adenyl cyclase (often activated by G-protein) cAMP acts like an intracellular hormone, stimulating variety of effects thatdiffers from tissue to tissue

Cyclic AMP Figure 11.9 O –O N O P OH CH2 NH2 ATP Ch2 H2O HO Adenylyl cyclase Phoshodiesterase Pyrophosphate Cyclic AMP AMP i

Many G-proteins trigger the formation of cAMP, which then acts as a second messenger in cellular pathways ATP GTP cAMP Protein kinase A Cellular responses G-protein-linked receptor Adenylyl cyclase G protein First messenger (signal molecule such as epinephrine) Figure 11.10

Calcium (another second messenger) Ca++ is an important second messenger because cells are able to regulate its concentration in the cytosol EXTRACELLULAR FLUID Plasma membrane ATP CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) Nucleus Mitochondrion Key High [Ca2+] Low [Ca2+] Figure 11.11 Other second messengers such as inositol triphosphate and diacylglycerol Can trigger an increase in calcium in the cytosol

Figure 11.12 3 2 1 4 6 5 EXTRA- CELLULAR FLUID Signal molecule 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 Figure 11.12

Response Response: Cell signaling leads to regulation of cytoplasmic activities or transcription Cells use multi step pathways for amplification Each activated component can turn “on”, or activate multiple copies of many different target molecules The more steps involved, the bigger the final number of activated products = activation cascade.

Binding of epinephrine to G-protein-linked receptor (1 molecule) Response Glucose-1-phosphate (108 molecules) Glycogen Active glycogen phosphorylase (106) Inactive glycogen phosphorylase Active phosphorylase kinase (105) Inactive phosphorylase kinase Inactive protein kinase A Active protein kinase A (104) ATP Cyclic AMP (104) Active adenylyl cyclase (102) Inactive adenylyl cyclase Inactive G protein Active G protein (102 molecules) Binding of epinephrine to G-protein-linked receptor (1 molecule) Transduction Response Reception - The different combinations of proteins in a cell give the cell great specificity in both the signals it detects and the responses it carries out Figure 11.13

Ex) Gene Regulation Other pathways regulate genes by activating transcription factors that turn genes on or off Reception Transduction Response mRNA NUCLEUS Gene P Active transcription factor Inactive DNA Phosphorylation cascade CYTOPLASM Receptor Growth factor Figure 11.14

Pathway branching and “cross-talk” Further help the cell coordinate incoming signals Response 1 Response 4 Response 5 Response 2 3 Signal molecule Cell A. Pathway leads to a single response Cell B. Pathway branches, leading to two responses Cell C. Cross-talk occurs between two pathways Cell D. Different receptor leads to a different response Activation or inhibition Receptor Relay molecules Figure 11.15

Termination of the Signal Signal response is terminated quickly By the reversal of ligand binding