Chapter 11

Cell CommunicationAP BiologyMs. Gaynor

External signals Cellular Responses

• Cells use Signal transduction pathways–Convert signals OUTSIDE cell cellular responses•Similar in microbes and mammals, suggesting an early origin

• http://www.dnalc.org/resources/3d/cellsignals.html

Why do cells use chemical signals? • To communicate without physical contact• Communication distant can be small OR

large

What happens when cells fail to communicate properly?

• Abnormal development, diseases, cancer, death

Why study cell communcation?• Allows humans to modify and change

pathways, create drugs to help diseases, control diseases, agriculture production, fruit ripening, etc.

Chemical Signals

• Cells communicate through chemical messengers

• Signal molecules (ligand)• growth factors• neurotransmitters• hormones (lipids) • peptides (small proteins)

»Lipid soluble and insoluble

Cell-cell recognition. Two cells in an animal may communicate by interaction between molecules protruding from their

surfaces.

• In local (short distance) signaling, cells may communicate via direct contact

• Animal and plant cells–have cell junctions that directly

connect the cytoplasm of adjacent cells

Plasma membranes

Plasmodesmatabetween plant cells

Gap junctionsbetween animal cells

Both animals and plants have cell junctions that allow molecules to pass readily between adjacent cells without crossing plasma membranes.

Bacteria & Cell-to-Cell Communcation

• Quorum sensing (short distance communication)– Bacteria secrete chemical signal helps

bacteria coordinate behavior– Regulation of gene expression in bacteria in

response to external stimuli.– Method used in response to population density

• Usually, multicellular organisms communicate using local regulators

Paracrine signaling. Secreting cell acts on nearby target cells by

discharging molecules of a local regulator (i.e. growth factor) into extracellular fluid.

Synaptic signaling A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell.

Local regulator diffuses through extracellular fluid

Target cell

Secretoryvesicle

Electrical signalalong nerve celltriggers release ofneurotransmitter

Neurotransmitter diffuses across

synapse

Target cell is stimulated

2 types of Local signaling

Figure 11.4 A B

• In long-distance signaling–Both plants and animals use hormones

Hormone travelsin bloodstreamto target cells

Animal Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all body cells.

Long-distance signalingBloodvessel

Targetcell

Endocrine cell

3 Stages of Cell Signaling• Earl W. Sutherland

–Discovered how the hormone epinephrine acts on cells

– http://highered.mcgraw-hill.com/olcweb/cgi/pluginpop.cgi?it=swf::535::535::/sites/dl/free/0072437316/120109/bio48.swf::Action%20of%20Epinephrine%20on%20a%20Liver%20Cell

– Sutherland suggested that cells receiving signals went through 3 processes

1. Reception2. Transduction3. Response

EXTRACELLULARFLUID

Receptor

Signal molecule

Relay molecules in a signal transduction pathway

Plasma membraneCYTOPLASM

Activationof cellularresponse

Figure 11.5

• Overview of cell signaling

Reception1

Transduction2

Response3

http://www.biosolutions.info/2008/01/signal-transduction.html

STEP #1: Reception• A signal molecule binds to a

receptor protein receptor changes shape

• Binding between signal (called ligand) & receptor protein is highly specific

»Changing shape initiates transduction of the signal

Receptors • Found in “target” cells• 2 types/ locations

1. cell membrane (most abundant) called plasma membrane receptors

1st Type of Receptors

Plasma membrane receptors

Chemical signal for these receptors can NOT pass THROUGH membrane…so it needs to be

hydrophilic. WHY?

2nd type of Receptors 2. inside cell called intracellular receptors

• Found in cytoplasm or nucleus

• Chemical signal needs to pass THROUGH membrane…so it needs to be hydrophobic. WHY?

Intracellular receptors (con’t)

• Signal molecules that are small or hydrophobic–WHY???–They can easily cross the plasma membrane •Ex: lipid soluble steriod/hormones (such as testosterone)

Specific Examples of Receptors Involved in Cell Communication

Hormone(testosterone)

EXTRACELLULAR FLUID

Receptorprotein

DNA

mRNA

NUCLEUS

CYTOPLASM

Plasmamembrane

Hormone-receptorcomplex

New protein for MALE

development

Figure 11.6

Example #1: Intracellular receptor– Ex: Steroid hormones

1 The steroid hormone testosterone passes through the plasma membrane.

The bound protein stimulates the transcription of the gene into mRNA.

4

The mRNA is translated into a specific protein.

5

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

Example #2, 3, 4: Cell Membrane Receptors

• There are 3 main types of membrane receptors1. G-protein-linked2. Tyrosine kinases3. Ion channel

Names based on how they work!

• G-Protein = short for guanine nucleotide (GTP)-binding proteins– Ex: used in embryonic development, growth,

smell, vision, over 60% of medications used today work by influencing G-protein pathways

1. G-protein-linked receptors

G-protein-linked receptors• All G-protein-linked receptors have

similar structure regardless of the organism in which they are found

• Made of alpha-helices• Signal-binding site on outside of cell• G-protein-interacting site on inside of

cell• http://highered.mcgraw-hill.com/sites/9834092339/student_view0/chapt

er9/signal_transduction_by_extracellular_receptors.html

–Ex: epinephrine• http://bcs.whfreeman.com/thelifewire/content/chp15/15020.html• http://www.dnatube.com/view_video.php?viewkey=b4d3fbd5ba2ce59211f5

2. Tyrosine kinase ReceptorSignalmolecule

Signal-binding sitea

CYTOPLASM

Tyrosines

Signal moleculeHelix in the

Membrane

Tyr

Tyr

Tyr

Tyr

Tyr

TyrTyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

DimerReceptor tyrosinekinase proteins(inactive monomers)

P

P

P

P

P

PTyr

Tyr

Tyr

Tyr

Tyr

TyrP

P

P

P

P

PCellularresponse 1

Inactiverelay proteins

Activatedrelay proteins

Cellularresponse 2

Activated tyrosine-kinase regions(unphosphorylateddimer)

Fully activated receptortyrosine-kinase(phosphorylateddimer)

6 ATP 6 ADP

Ex: used cell growth and development, reproduction

• Part of the Tyrosine Kinase receptor on cytoplasmic side serves as an enzyme –Catalyzes transfer of Pi’s from ATP to

amino acid Tyrosine on substrate

http://www.wiley.com/college/fob/quiz/quiz21/21-15.html

3. Ion channel receptors

Cellularresponse

Gate open

Gate close

Ligand-gatedion channel receptor

Plasma Membrane

Signal molecule(ligand)

Gate closedIons

Ex: used in nervous system

http://highered.mcgraw-hill.com/sites/0072495855/student_view0/chapter2/animation__receptors_linked_to_a_channel_protein.html

STEP #2: Transduction(converting the signal)

• Cascades of molecular interactions relay signals from receptors to target molecules in the cell

• Multistep pathways–Can amplify a signal–Provide more opportunities for coordination and regulation

Signal Transduction Pathways

• At each step in a pathway–signal is transduced (converted) into a different form USUALLY a conformational change in a protein using…

–Protein Phosphorylation and Dephosphorylation

• In this process–A series of protein kinases add a phosphate to the next one in line, activating it• VERY IMPORTANT ~2% of our genes

• Single cell has 100’s of different kinds of kinases (substrate specific)

–Phosphatase enzymes then remove the phosphates

Signal molecule

Activeproteinkinase

1

Activeproteinkinase

2

Activeproteinkinase

3

Inactiveprotein kinase

1

Inactiveprotein kinase

2

Inactiveprotein kinase

3

Inactiveprotein

Activeprotein

Cellularresponse

Receptor

P

P

P

ATP

ADP

ADP

ADP

ATP

ATP

PP

PP

PP

Activated relaymolecule

i

Phosphorylation cascade

P 

P

i

i

P

A phosphorylation cascade: like a Pi relay!!

Figure 11.8

A relay moleculeactivates protein kinase 1.

1

2 Active protein kinase 1transfers a phosphate from ATPto an inactive molecule ofprotein kinase 2, thus activatingthis second kinase.

Active protein kinase 2then catalyzes the phos-phorylation (and activation) ofprotein kinase 3.

3

Finally, active proteinkinase 3 phosphorylates aprotein (pink) that brings about the cell’s response tothe signal.

4 Enzymes called proteinphosphatases (PP)catalyze the removal ofthe phosphate groupsfrom the proteins, making them inactiveand available for reuse.

5

Small Molecules and Ions act as Second Messengers

• Second messengers–Are small, nonprotein, water-soluble molecules or ionsEx: cAMP (cyclic AMP), Ca2+, IP3

http://highered.mcgraw-hill.com/sites/9834092339/stude

nt_view0/chapter9/second_messenger__camp.html

Cyclic AMP • Cyclic AMP (cAMP)

– Is made from ATP by adenylyl cyclase (but cAMP is short lived!)

O

–O O

O

N

O

O

O

O

P P P

P

P P

O

O

O

O

O

OH

CH2

NH2 NH2 NH2

N

N

N

N

N

N

N

N

N

N

NO

O

O

ATP

Ch2CH2

O

OH OH

P

O O

H2O

HO

Adenylyl cyclase Phoshodiesterase

Pyrophosphate

Cyclic AMP AMP

OH OH

O

i

• Many G-proteins– Trigger the formation of cAMP, which

then acts as a second messenger in cellular pathways

ATP

GTP

cAMP

Proteinkinase A

Cellular responses

G-protein-linkedreceptor

AdenylylcyclaseG protein

First messenger(signal moleculesuch as epinephrine)

Figure 11.10

CAFFEINE BLOCKS cAMP AMP BY PHOPHODIESTERASE SO cAMP LEVELS REMAIN HIGH

Other Secondary Messagers…

• Inositol triphosphate (IP3)–Triggers increase in calcium

ions in the cytosol by inducing the release of Ca+2 from the ER

• Calcium (Ca+2)• Ex: involved in muscle contractions

Figure 11.12

321

IP3 quickly diffuses throughthe cytosol and binds to an IP3–gated calcium channel in the ERmembrane, causing it to open.

4 The calcium ionsactivate the nextprotein in one or moresignaling pathways.

6 Calcium ions flow out ofthe ER (down their con-centration gradient), raisingthe Ca2+ level in the cytosol.

5

DAG functions asa second messengerin other pathways.

Phospholipase C cleaves aplasma membrane phospholipidcalled PIP2 into DAG and IP3.

A signal molecule bindsto a receptor, leading toactivation of phospholipase C.

EXTRA-CELLULARFLUID

Signal molecule(first messenger)

G protein

G-protein-linkedreceptor

Variousproteinsactivated

Endoplasmicreticulum (ER)

Phospholipase C

PIP2

IP3

(second messenger)

DAG

Cellularresponse(muscle contraction)

GTP

Ca2+

(second messenger)

Ca2+

IP3-gatedcalcium channel

STEP #3: Response• Cell signaling leads to:1. regulation of cytoplasmic

activities or 2. nuclear activities

– Ex: transcription» DNA mRNA

» http://highered.mcgraw-hill.com/sites/9834092339/student_view0/chapter9/intracellular_receptor_model.html

• Cytoplasmic response to a signal

Figure 11.13

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

Signal Amplification• Each protein in a

signaling pathway– Amplifies (continues)

signal by activating multiple copies of next component in the pathway

– Can be many or few proteins in cascasde

• Other pathways– Regulate genes by activating

transcription factors that turn genes on or off Reception

Transduction

Response

mRNANUCLEUS

Gene

P

Activetranscriptionfactor

Inactivetranscriptionfactor

DNA

Phosphorylationcascade

CYTOPLASM

Receptor

Growth factor

Figure 11.14

http://highered.mcgraw-hill.com/sites/9834092339/student_view0/chapter9/how_intracellular_receptors_regulate_gene_transcription.html

• Pathway branching and “cross-talk”– Further help the cell coordinate incoming signals

Response 1

Response 4 Response 5

Response

2

Response

3

Signalmolecule

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 receptorleads to a different response

Activationor inhibition

Receptor

Relaymolecules

Figure 11.15

Signaling Efficiency: Scaffolding Proteins and Signaling Complexes

• Scaffolding proteins– Can increase the signal transduction

efficiency

Signalmolecule

Receptor

Scaffoldingprotein

Threedifferentproteinkinases

Plasmamembrane

Figure 11.16

Termination of the Signal• Signal response is terminated quickly

–By the reversal of ligand binding

INACTIVE- TURNED “OFF”

ACTIVE- TURNED “ON”

When things go wrong…

• Diabetes• Heart disease• Neurological or autoimmune

disorders• Cancer• Death (ex: from neurotoxins,

poisons, pesticides)

Great tutorial to use to study…

• http://www.biology.arizona.edu/CELL_BIO/problem_sets/signaling/04q.html