Chapter 11 Cell Communication

Overview: The Cellular Internet Cell-to-cell communication is essential for multicellular organisms Biologists have discovered some universal mechanisms of cellular regulation

Concept 11.1: External signals are converted into responses within the cell Microbes are a window on the role of cell signaling in the evolution of life

Evolution of Cell Signaling A signal-transduction pathway is a series of steps by which a signal on a cell’s surface is converted into a specific cellular response Signal transduction pathways convert signals on a cell’s surface into cellular responses Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and have since been adopted by eukaryotes

LE 11-2 Exchange of mating factors a factor Receptor a a a factor Yeast cell, mating type a Yeast cell, mating type a Mating a a New a/a cell a/a

Local and Long-Distance Signaling Cells in a multicellular organisms communicate by chemical messengers Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells In local signaling, animal cells may communicate by direct contact

LE 11-3 Plasma membranes Gap junctions between animal cells Plasmodesmata between plant cells Cell junctions Cell-cell recognition

In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances In long-distance signaling, plants and animals use chemicals called hormones

LE 11-4 Local signaling Long-distance signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter Endocrine cell Blood vessel Neurotransmitter diffuses across synapse Secreting cell Secretory vesicle Hormone travels in bloodstream to target cells Local regulator diffuses through extracellular fluid Target cell is stimulated Target cell Paracrine signaling Synaptic signaling Hormonal signaling

The Three Stages of Cell Signaling: A Preview Earl W. Sutherland discovered how the hormone epinephrine acts on cells Sutherland suggested that cells receiving signals went through three processes: Reception Transduction Response Animation: Overview of Cell Signaling

LE 11-5_1 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Receptor Signal molecule

Relay molecules in a signal transduction EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Receptor Relay molecules in a signal transduction pathway Signal molecule

Relay molecules in a signal transduction EXTRACELLULAR FLUID CYTOPLASM Plasma membrane Reception Transduction Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Signal molecule

Concept 11.2: Reception: A signal molecule binds to a receptor protein, causing it to change shape The binding between a signal molecule (ligand) and receptor is highly specific A conformational change in a receptor is often the initial transduction of the signal Most signal receptors are plasma membrane proteins

Intracellular Receptors Some receptor proteins are intracellular, 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

LE 11-6 Hormone EXTRACELLULAR (testosterone) FLUID The steroid hormone testosterone passes through the plasma membrane. Plasma membrane Testosterone binds to a receptor protein in the cytoplasm, activating it. Receptor protein Hormone- receptor complex The hormone- receptor complex enters the nucleus and binds to specific genes. DNA mRNA The bound protein stimulates the transcription of the gene into mRNA. NUCLEUS New protein The mRNA is translated into a specific protein. CYTOPLASM

Receptors in the Plasma Membrane Most water-soluble signal molecules bind to specific sites on receptor proteins in the plasma membrane There are three main types of membrane receptors: G-protein-linked receptors Receptor tyrosine kinases Ion channel receptors

A G-protein-linked receptor is a plasma membrane receptor that works with the help of a G protein The G-protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive

G-protein-linked receptor LE 11-7aa Signal-binding site Segment that interacts with G proteins G-protein-linked receptor

Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines A receptor tyrosine kinase can trigger multiple signal transduction pathways at once

LE 11-7b Signal molecule Signal-binding site a Helix in the membrane Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Receptor tyrosine kinase proteins (inactive monomers) Dimer CYTOPLASM Activated relay proteins Cellular response 1 Tyr Tyr P Tyr P Tyr P Tyr Tyr P Tyr Tyr P Tyr Tyr P P P Tyr Tyr Tyr Tyr P Tyr Tyr P P Tyr Tyr P Cellular response 2 6 ATP 6 ADP Activated tyrosine- kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine-kinase (phosphorylated dimer) Inactive relay proteins

An ion channel receptor acts as a gate when the receptor changes 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

LE 11-7c Signal molecule (ligand) Gate closed Ions Plasma membrane Ligand-gated ion channel receptor Gate open Cellular response Gate closed

Transduction usually involves multiple steps Concept 11.3: Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell Transduction usually involves multiple steps Multistep pathways can amplify a signal: A few molecules can produce a large cellular response Multistep pathways provide more opportunities for coordination and regulation

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

Protein Phosphorylation and Dephosphorylation In many pathways, the signal is transmitted by a cascade of protein phosphorylations Phosphatase enzymes remove the phosphates This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off

LE 11-8 Signal molecule Receptor Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP ADP Active protein kinase 2 P Phosphorylation cascade PP P i 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 Second messengers are small, nonprotein, water-soluble molecules or ions The extracellular signal molecule that binds to the membrane is a pathway’s “first messenger” Second messengers can readily spread throughout cells by diffusion Second messengers participate in pathways initiated by G-protein-linked receptors and receptor tyrosine kinases

Cyclic AMP Cyclic AMP (cAMP) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal

LE 11-9 Pyrophosphate ATP Cyclic AMP AMP Adenylyl cyclase Phosphodiesterase Pyrophosphate H2O P P i ATP Cyclic AMP AMP

Many signal molecules trigger formation of cAMP Other components of cAMP pathways are G proteins, G-protein-linked receptors, and 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

LE 11-10 First messenger (signal molecule such as epinephrine) Adenylyl cyclase G protein G-protein-linked receptor GTP ATP Second messenger cAMP Protein kinase A Cellular responses

Calcium ions and Inositol Triphosphate (IP3) Calcium ions (Ca2+) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration

LE 11-11 EXTRACELLULAR FLUID Plasma membrane Ca2+ pump ATP Mitochondrion Nucleus CYTOSOL Ca2+ pump Endoplasmic reticulum (ER) ATP Ca2+ pump Key High [Ca2+] Low [Ca2+]

Animation: Signal Transduction Pathways 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 second messengers Animation: Signal Transduction Pathways

EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG GTP G-protein-linked receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) Ca2+ CYTOSOL

EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG GTP G-protein-linked receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) Ca2+ Ca2+ (second messenger) CYTOSOL

EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG GTP G-protein-linked receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Cellular re- sponses Various proteins activated Endoplasmic reticulum (ER) Ca2+ Ca2+ (second messenger) CYTOSOL

Concept 11.4: Response: Cell signaling leads to regulation of cytoplasmic activities or transcription The cell’s response to an extracellular signal is sometimes called the “output response”

Cytoplasmic and Nuclear Responses Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities The response may occur in the cytoplasm or may involve action in the nucleus Many pathways regulate the activity of enzymes

LE 11-13 Reception Binding of epinephrine to G-protein-linked receptor (1 molecule) Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose-1-phosphate (108 molecules)

Many other signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus The final activated molecule may function as a transcription factor

LE 11-14 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Response P DNA Gene NUCLEUS mRNA

Fine-Tuning of the Response Multistep pathways have two important benefits: Amplifying the signal (and thus the response) Contributing to the specificity of the response

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

The Specificity of Cell Signaling Different kinds of cells have different collections of proteins These differences in proteins give each kind of cell specificity in detecting and responding to signals The response of a cell to a signal depends on the cell’s particular collection of proteins Pathway branching and “cross-talk” further help the cell coordinate incoming signals

LE 11-15 Signal molecule Receptor Relay molecules Response 1 Cell A. Pathway leads to a single response Cell B. Pathway branches, leading to two responses Activation or inhibition Response 4 Response 5 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 Scaffolding proteins can increase the signal transduction efficiency

Signal Plasma molecule membrane Receptor Three different protein kinases Scaffolding protein

Termination of the Signal Inactivation mechanisms are an essential aspect of cell signaling When signal molecules leave the receptor, the receptor reverts to its inactive state