Cellular Communication Chapter 11 Cellular Communication I think she meant a different kind of cellular communication… Don’t you get it? It’s what I meant to say, not what I really said!… We eat to take in the fuels to make ATP which will then be used to help us build biomolecules and grow and move and… live! heterotrophs = “fed by others” vs. autotrophs = “self-feeders”

External signals are converted to responses within the cell  factor External signals are converted to responses within the cell Yeast has two mating types, a and  Cells locate each other via secreted factors Signal Transduction Pathway series of steps that convert a signal on a cell’s surface into a specific cellular response.  factor Receptor 1 Exchange of mating factors a  Yeast cell, mating type a a factor Yeast cell, mating type  2 a  Mating 3 a/ New a/ cell © 2011 Pearson Education, Inc.

© 2011 Pearson Education, Inc. Pathway similarities suggest ancestral signaling molecules evolved in prokaryotes and later modified in eukaryotes. Signal molecule concentration allows bacteria to sense population density. Common trait, common ancestry… © 2011 Pearson Education, Inc.

Individual rod-shaped cells Figure 11.3 1 Individual rod-shaped cells 2 Aggregation in progress 0.5 mm 3 Spore-forming structure (fruiting body) 2.5 mm Figure 11.3 Communication among bacteria. Fruiting bodies

Long-Distance and Local Signaling Cells in a multicellular organism communicate by chemical messengers. Animal and plant cells use cell junctions directly connect cytoplasm of adjacent cells And Local signaling communication by direct contact, or by cell-cell recognition Plasma membranes Gap junctions between animal cells Plasmodesmata between plant cells (a) Cell junctions (b) Cell-cell recognition © 2011 Pearson Education, Inc. (b) Cell-cell recognition

Long-Distance Signaling Endocrine cell Blood vessel Long-Distance Signaling plants and animals use chemicals called hormones The ability of a cell to respond to a signal depends on presence of the receptor specific to that signal Hormone travels in bloodstream. Target cell specifically binds hormone. (c) Endocrine (hormonal) signaling © 2011 Pearson Education, Inc.

Local Signaling messenger molecules that travel only short distances Electrical signal along nerve cell triggers release of neurotransmitter. Target cell Neurotransmitter diffuses across synapse. Secreting cell Secretory vesicle Local regulator diffuses through extracellular fluid. Target cell is stimulated. (a) Paracrine signaling (b) Synaptic signaling © 2011 Pearson Education, Inc.

Three Stages of Cell Signaling: Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes Reception Transduction Response © 2011 Pearson Education, Inc.

© 2011 Pearson Education, Inc. Animation: Overview of Cell Signaling Right-click slide / select “Play” © 2011 Pearson Education, Inc. 9

Figure 11.6-1 Reception: signaling molecule binds to receptor protein, causing conformation change. The binding between a signal molecule (ligand) and receptor is highly specific A shape change in a receptor is often the initial transduction of the signal Most signal receptors are plasma membrane proteins Plasma membrane EXTRACELLULAR FLUID CYTOPLASM Reception Receptor Signaling molecule 1 EXTRACELLULAR FLUID EXTRACELLULAR FLUID CYTOPLASM CYTOPLASM Plasma membrane Plasma membrane 1 1 Reception Reception 2 2 Transduction Transduction 3 Response Receptor Receptor Activation of cellular response Figure 11.6 Overview of cell signaling. Relay molecules in a signal transduction pathway Relay molecules in a signal transduction pathway Signaling molecule Signaling molecule

Types of Receptors in the Plasma Membrane Water-soluble signal molecules bind to specific sites on receptor proteins that span the plasma membrane There are three main types of membrane receptors G protein-coupled receptors Receptor tyrosine kinases Ion channel receptors © 2011 Pearson Education, Inc.

© 2011 Pearson Education, Inc. G protein-coupled receptors (GPCRs) Largest family of cell-surface receptors. Works with the help of a G protein (Guanine nucleotide- binding proteins) - acts as an on/off switch. “off” when bound to GDP (Guanine diphosphate) “on” when bound to GTP (Guanine triphosphate) You know what turns me on! …and off! © 2011 Pearson Education, Inc.

G protein-coupled receptor Signaling molecule binding site Figure 11.7a G protein-coupled receptor Signaling molecule binding site Segment that interacts with G proteins Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors

G protein-coupled receptor Figure 11.7b G protein-coupled receptor 2 1 3 4 Plasma membrane G protein (inactive) CYTOPLASM Enzyme Activated receptor Signaling molecule Inactive enzyme Activated enzyme Cellular response GDP GTP P i Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors http://www.youtube.com/watch?v=4dUJ5GNpfrA&feature=endscreen&NR=1

© 2011 Pearson Education, Inc. Receptor tyrosine kinases (RTKs) receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once Abnormal functioning of RTKs is associated with many types of cancers © 2011 Pearson Education, Inc.

Receptor tyrosine kinase Figure 11.7c Signaling molecule (ligand) Ligand-binding site  helix in the membrane Signaling molecule Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr CYTOPLASM Receptor tyrosine kinase Proteins (inactive monomers) Dimer 1 2 Activated relay proteins Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors Cellular response 1 Tyr Tyr P Tyr Tyr P Tyr Tyr P P Tyr Tyr P Tyr Tyr P Tyr Tyr P P Cellular response 2 Tyr Tyr P Tyr Tyr P Tyr Tyr P 6 ATP 6 ADP P Activated tyrosine kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine kinase (phosphorylated dimer) Inactive relay proteins 3 4

© 2011 Pearson Education, Inc. Ligand-gated ion channel receptors acts as gates when the receptors change shape. When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor © 2011 Pearson Education, Inc.

Signaling molecule (ligand) Ligand-gated ion channel receptor Figure 11.7d 1 2 3 Gate closed Ions Gate open Gate closed Signaling molecule (ligand) Plasma membrane Ligand-gated ion channel receptor Cellular response Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors

Intracellular Receptors Intracellular receptor proteins are found in the cytosol or nucleus of target cells Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors Examples of hydrophobic messengers are the steroid and thyroid hormones of animals An activated hormone-receptor complex can act as a transcription factor, turning on specific genes © 2011 Pearson Education, Inc.

I like this Testosterone stuff! Figure 11.9-1 Hormone (testosterone) Receptor protein Plasma membrane Hormone- receptor complex DNA NUCLEUS CYTOPLASM EXTRACELLULAR FLUID Hormone (testosterone) Receptor protein Plasma membrane Hormone- receptor complex DNA NUCLEUS CYTOPLASM EXTRACELLULAR FLUID Hormone (testosterone) Receptor protein Plasma membrane DNA NUCLEUS CYTOPLASM EXTRACELLULAR FLUID Hormone (testosterone) Receptor protein Plasma membrane Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM EXTRACELLULAR FLUID Hormone (testosterone) Receptor protein Plasma membrane EXTRACELLULAR FLUID Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM New protein I like this Testosterone stuff! Figure 11.9 Steroid hormone interacting with an intracellular receptor.

Hormone (testosterone) Hormone- receptor complex Figure 11.9-5 Hormone (testosterone) Receptor protein Plasma membrane EXTRACELLULAR FLUID Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM New protein 1. 2. 3. 4. Figure 11.9 Steroid hormone interacting with an intracellular receptor. 5. 6.

© 2011 Pearson Education, Inc. Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell Signal transduction usually involves multiple steps Can amplify a signal: A few molecules can produce a large cellular response provide more opportunities for coordination and regulation of the cellular response © 2011 Pearson Education, Inc.

Signal Transduction Pathways The molecules that relay a signal from receptor to response are mostly proteins. Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated. At each step, the signal is transduced into a different form, usually a conformational change in a protein. © 2011 Pearson Education, Inc.

Protein Phosphorylation and Dephosphorylation In many pathways, the signal is transmitted by a cascade of protein phosphorylations. Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation. © 2011 Pearson Education, Inc.

© 2011 Pearson Education, Inc. Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation. This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off or up or down, as required. © 2011 Pearson Education, Inc.

Activated relay molecule Phosphorylation cascade Figure 11.10a Signaling molecule Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP Phosphorylation cascade ADP Active protein kinase 2 P PP P i Figure 11.10 A phosphorylation cascade. Inactive protein kinase 3 ATP ADP Active protein kinase 3 P PP P i Inactive protein ATP ADP P Active protein Cellular response PP P i

Small Molecules and Ions as Second Messengers “First messenger” - extracellular signal molecule (ligand) binds to the receptor. Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion. ex. - Cyclic AMP and calcium ions Second messengers participate in pathways initiated by GPCRs and RTKs © 2011 Pearson Education, Inc.

© 2011 Pearson Education, Inc. Cyclic AMP Cyclic AMP (cAMP) - widely used second messenger. Adenylyl cyclase converts ATP to cAMP in response to an extracellular signal. Adenylyl cyclase Phosphodiesterase Pyrophosphate AMP H2O ATP P i P cAMP © 2011 Pearson Education, Inc.

© 2011 Pearson Education, Inc. Many signal molecules trigger formation of cAMP. Components of cAMP pathways: a) G proteins b) G protein-coupled receptors c) protein kinases cAMP usually activates protein kinase A, which phosphorylates various other proteins. Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase (which shuts down cAMP production). © 2011 Pearson Education, Inc.

First messenger (signaling molecule such as epinephrine) Figure 11.12 First messenger (signaling molecule such as epinephrine) Adenylyl cyclase G protein G protein-coupled receptor GTP ATP Second messenger cAMP Figure 11.12 cAMP as a second messenger in a G protein signaling pathway. Protein kinase A Cellular responses

Calcium Ions and Inositol Triphosphate (IP3) Mitochondrion EXTRACELLULAR FLUID Plasma membrane Ca2 pump Nucleus CYTOSOL Endoplasmic reticulum (ER) ATP Low [Ca2 ] High [Ca2 ] Key Calcium ions (Ca2+) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration © 2011 Pearson Education, Inc.

Endoplasmic reticulum (ER) Figure 11.13 Mitochondrion EXTRACELLULAR FLUID Plasma membrane Ca2 pump Nucleus CYTOSOL Endoplasmic reticulum (ER) ATP Low [Ca2 ] High [Ca2 ] Key Figure 11.13 The maintenance of calcium ion concentrations in an animal cell.

© 2011 Pearson Education, Inc. A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers © 2011 Pearson Education, Inc.

© 2011 Pearson Education, Inc. Animation: Signal Transduction Pathways Right-click slide / select “Play” © 2011 Pearson Education, Inc. 34

Signaling molecule (first messenger) Figure 11.14-3 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.14 Calcium and IP3 in signaling pathways. Various proteins activated Cellular responses Endoplasmic reticulum (ER) Ca2 Ca2 (second messenger) CYTOSOL

Nuclear and Cytoplasmic Responses Signal transduction pathway leads to regulation of one or more cellular activities Response may occur in the cytoplasm or in the nucleus Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus The final activated molecule in the signaling pathway may function as a transcription factor. © 2011 Pearson Education, Inc.

Inactive transcription factor Active transcription factor Figure 11.15 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Figure 11.15 Nuclear responses to a signal: the activation of a specific gene by a growth factor. Response P DNA Gene NUCLEUS mRNA

© 2011 Pearson Education, Inc. Other pathways regulate the activity of enzymes rather than their synthesis Signaling pathways can also affect the overall behavior of a cell, for example, changes in cell shape © 2011 Pearson Education, Inc.

Fine-Tuning of the Response There are four aspects of fine-tuning to consider Amplification of the signal Specificity of the response Overall efficiency of response, enhanced by scaffolding proteins Termination of the signal © 2011 Pearson Education, Inc.

© 2011 Pearson Education, Inc. Signal Amplification Enzyme cascades amplify the cell’s response. At each step, the number of activated products is much greater than in the preceding step. © 2011 Pearson Education, Inc.

The Specificity of Cell Signaling and Coordination of the Response Different kinds of cells have different collections of proteins These different proteins allow cells to detect and respond to different signals Even the same signal can have different effects in cells with different proteins and pathways Pathway branching and “cross-talk” further help the cell coordinate incoming signals © 2011 Pearson Education, Inc.

Activation or inhibition Figure 11.18 Signaling molecule Receptor Relay molecules Activation or inhibition Figure 11.18 The specificity of cell signaling. Response 1 Response 2 Response 3 Response 4 Response 5 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.

Signaling Efficiency: Scaffolding Proteins and Signaling Complexes Scaffolding proteins are large relay proteins to which other relay proteins are attached Increase the signal transduction efficiency by grouping together proteins involved in the same pathway May also help activate some of the relay proteins © 2011 Pearson Education, Inc.

Three different protein kinases Figure 11.19 Signaling molecule Plasma membrane Receptor Three different protein kinases Figure 11.19 A scaffolding protein. Scaffolding protein

Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling. If ligand concentration falls, fewer receptors will be bound. Unbound receptors revert to an inactive state. © 2011 Pearson Education, Inc.

Apoptosis integrates multiple cell-signaling pathways Apoptosis is programmed or controlled cell suicide Components of the cell are chopped up and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells © 2011 Pearson Education, Inc.

Apoptotic Pathways and the Signals That Trigger Them Caspases -the main proteases (enzymes that cut up proteins) that carry out apoptosis Apoptosis can be triggered by An extracellular death-signaling ligand DNA damage in the nucleus Protein misfolding in the endoplasmic reticulum © 2011 Pearson Education, Inc.

Cells undergoing apoptosis Apoptosis evolved early in animal evolution and is essential for the development and maintenance of all animals Apoptosis may be involved in some diseases (for example, Parkinson’s and Alzheimer’s); interference with apoptosis may contribute to some cancers Interdigital tissue Cells undergoing apoptosis Space between digits 1 mm © 2011 Pearson Education, Inc.