The Cellular Internet

• Cell-to-cell communication is essential for multicellular organisms

• Biologists have discovered some universal mechanisms of cellular regulation

Exchange ofmating factors

Mating

Receptor

a

factor

a

a factorYeast cell,mating type a

Yeast cell,mating type

a/

New a/ cell

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

• 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

Plasma membranes

Gap junctionsbetween animal cells

Cell junctions

Cell-cell recognition

Plasmodesmatabetween plant cells

Paracrine signaling

Local regulatordiffuses throughextracellular fluid

Secretoryvesicle

Secretingcell

Target cell

Local signaling

Electrical signalalong nerve celltriggers release ofneurotransmitter

Neurotransmitter diffuses across synapse

Endocrine cell Bloodvessel

Long-distance signaling

Hormone travelsin bloodstreamto target cells

Synaptic signaling

Target cellis stimulated

Hormonal signaling

Target cell

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 3 processes:

– Reception

– Transduction

– Response

EXTRACELLULARFLUID

Reception

Plasma membrane

Transduction

CYTOPLASM

Receptor

Signalmolecule

Relay molecules in a signal transductionpathway

Response

Activationof cellularresponse

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

EXTRACELLULARFLUID

Plasmamembrane

The steroidhormone testosteronepasses through theplasma membrane.

Testosterone bindsto a receptor proteinin the cytoplasm,activating it.

The hormone-receptor complexenters the nucleusand binds to specificgenes.

The bound proteinstimulates thetranscription ofthe gene into mRNA.

The mRNA istranslated into aspecific protein.

CYTOPLASM

NUCLEUS

DNA

Hormone(testosterone)

Receptorprotein

Hormone-receptorcomplex

mRNA

New protein

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

Segment thatinteracts withG proteins

Signal-binding site

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

• A kinase, alternatively known as a phosphotransferase, is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates. The process is referred to as phosphorylation.

Signalmolecule

Helix in themembrane

Signal-binding site

Tyr

Tyr

Tyr Tyr

Tyr

TyrTyrosines

Receptor tyrosinekinase proteins(inactive monomers)CYTOPLASM

Tyr

Tyr

Tyr Tyr

Tyr

Tyr Tyr

Tyr

Tyr Tyr

Tyr

Tyr

Tyr

Tyr

Tyr Tyr

Tyr

Tyr

Activated tyrosine-kinase regions(unphosphorylateddimer)

Signalmolecule

Dimer

Fully activated receptor tyrosine-kinase(phosphorylateddimer)

Tyr

Tyr

Tyr Tyr

Tyr

TyrPPP

PPPATP 6 ADP

Tyr

Tyr

Tyr Tyr

Tyr

TyrP

PP

PPP

Inactiverelay proteins

Cellularresponse 2

Cellularresponse 1

Activated relay proteins

6

http://upload.wikimedia.org/wikipedia/commons/8/8c/Insulin_glucose_metabolism.jpg

• 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

Signalmolecule(ligand)

Gateclosed Ions

Ligand-gatedion channel receptor

Plasmamembrane

Gate closed

Gate open

Cellularresponse

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 (kinases) and dephosphorylation (phosphatases) system acts as a molecular switch, turning activities on and off

Signal molecule

Activated relaymolecule

Receptor

Inactiveprotein kinase

1 Activeprotein kinase

1

Inactiveprotein kinase

2 Activeprotein kinase

2

Inactiveprotein kinase

3 Activeprotein kinase

3

ADP

Inactiveprotein

Activeprotein

Cellularresponse

Phosphorylation cascade

ATP

PPP i

ADPATP

PPP i

ADPATP

PPP i

P

P

P

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

ATP Cyclic AMP AMP

Adenylyl cyclase

PyrophosphateP P i

Phosphodiesterase

H2O

• 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

cAMP

ATPSecondmessenger

First messenger(signal moleculesuch as epinephrine)

G-protein-linkedreceptor

G protein

Adenylylcyclase

Proteinkinase A

Cellular responses

GTP

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

ATP

EXTRACELLULARFLUID

ATP

Mitochondrion

Ca2+

pump

Plasmamembrane

CYTOSOL

Endoplasmicreticulum (ER)

Ca2+

pump

Ca2+

pump

High [Ca2+]Key

Nucleus

Low [Ca2+]

• 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

CYTOSOL

Ca2+Endoplasmicreticulum (ER)

IP3-gatedcalcium channel

IP3 (secondmessenger)

DAG

PIP2G-protein-linkedreceptor Phospholipase C

G protein

Signal molecule(first messenger)

EXTRACELLULARFLUID

GTP

Ca2+ (secondmessenger)

Variousproteinsactivated

Cellularre-sponses

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

Binding of epinephrine to G-protein-linked receptor (1 molecule)

Reception

Transduction

Inactive G protein

Active G protein (102 molecules)

Inactive adenylyl cyclase

Active adenylyl cyclase (102)

ATP

Cyclic AMP (104)

Inactive protein kinase A

Inactive phosphorylase kinase

Active protein kinase A (104)

Active phosphorylase kinase (105)

Active glycogen phosphorylase (106)

Inactive glycogen phosphorylase

Glycogen

Response

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

ReceptionGrowth factor

Receptor

Phosphorylationcascade

Transduction

CYTOPLASM

Inactivetranscriptionfactor

Activetranscriptionfactor

PResponse

Gene

mRNA

DNA

NUCLEUS

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

Signalmolecule

Receptor

Relaymolecules

Response 1 Response 2 Response 3

Cell B. Pathway branches,leading to two responses

Cell A. Pathway leads to a single response

Cell C. Cross-talk occursbetween two pathways

Response 4 Response 5

Activationor inhibition

Cell D. Different receptorleads 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

Signalmolecule

Plasmamembrane

Receptor

Scaffoldingprotein

Threedifferentproteinkinases

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

Animations and Videos

• Biomembranes II: Membrane Dynamics and Communication

• Bozeman - Cell Communication

• Bozeman - Evolutionary Significance of Cell Communication

• Cell Junctions

• Tight Junctions

• Desmosomes

• Gap Junctions

Animations and Videos

• Bozeman - Signal Transduction

• Second Messengers (cAMP and Ca+2 Pathways)

• Chemical Synapse – 1

• Chemical Synapse – 2

• Voltage-Gated Channels and the Action Potential

• Signal Transduction Pathway

• Signaling by Secreted Molecules

• Signal Transduction

Animations and Videos

• 2nd Messenger

• Signal Amplification – 1

• Signal Amplification – 2

• Hormonal Communication

• Mechanism of Steroid Hormone Action

• Mechanism of Thyroxine Action

• Action of Epinephrine on a Liver Cell

• Action of Glucocorticoid Hormone

Animations and Videos

• Intracellular Receptor Model

• Mechanism of Action of Lipid-Soluble Messengers

• Mechanism of Thyroxine Action

• Mechanism of Steroid Hormone Action

• Lipid Soluble Hormone

• Chapter Quiz Questions – 1

• Chapter Quiz Questions - 2