How cells detect, process, and respond to chemical How cells detect, process, and respond to chemical signals send from other cells or from changes in the signals send from other cells or from changes in the physical environment ?physical environment ?

Chapter 11

Cell communication

Chapter 11

Cell communication

• Overview: The Cellular InternetOverview: The Cellular Internet

• Cell-to-cell communication

– Is absolutely essential for multicellular organisms

– External signals are converted into responses within the cell

Ex. Yeast cells --- Identify their mates by cell signaling

Cell signaling evolved early in the history of lifeCell signaling evolved early in the history of life

Saccharomyces cerevisiae “yeast” --- identify their mates by chemical signaling

Two sex,(mating type)

Without actually entering the cells, the receptor-bound molecules of the two mating factors cause the cells to grow toward each other and bring about other cellullar changes.

factorReceptor

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

factorYeast cell,mating type a

Yeast cell,mating type

a/

a

a

Figure 11.2

The process by which a signal on a cell’s surface

is converted into a specific cellular response is a

series of steps

--- called a signal-transduction pathway

• Signal transduction pathwaysSignal transduction pathways– Convert signals on a cell’s surface into cellular responseConvert signals on a cell’s surface into cellular response

ss– Are similar in microbes and mammals, suggesting an earlAre similar in microbes and mammals, suggesting an earl

y originy origin– Cells in a multicellular organism --- communicate via che

mical messengers

• Animal and plant cells

– Have cell junctions that directly connect the cytoplasm of adjacent cells

Plasma membranes

Plasmodesmatabetween plant cells

Gap junctionsbetween 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.

Figure 11.3(b) Cell-cell recognition. Two cells in an animal may communicate by interaction between molecules protruding from their surfaces.

• In local signaling, animal cells– May communicate via direct contact

• 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

Secretoryvesicle

Electrical signalalong nerve celltriggers release ofneurotransmitter

Neurotransmitter diffuses across

synapse

Target cellis stimulated

Local signaling

Figure 11.4 A B

Growth factorGrowth factor neurotransmitterneurotransmitter

Paracrine signaling:--- the transmitting cell secretes molecules of a local regulator a substance that influences cells in the vicinity.

• In long-distance signaling

– Both plants and animals use hormones

Hormone travelsin bloodstreamto 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

Bloodvessel

Targetcell

Endocrine cell

Figure 11.4 C

* Endocrine signaling: (animal cells)

--- specialized cells release hormone

molecules

into vessels of the circulatory system.

* In plants, hormones sometimes travel in

vessels

but more often reach their targets by

moving

through cells or by diffusion

through the air as a gas.

The plant hormone ethylene, a

gas that promotes fruit

ripening and helps regulate

growth.

(C2H4)

What happens when a cell encounters a signal ?

The signal must be recognized by a specific receptor molecule, and the information it carries must be changed into another form-transduced-inside the cell before the cell can respond.

The three stages of cell signaling are

reception, transduction, response

Earl W. Sutherland (Nobel Prize in 1971)

How the animal hormone epinephrine stimulates

breakdown of the storage polysaccharide

glycogen within liver and skeletal muscle cells.

Glycogen

Glucose-1-phosphate

Glucose-6-phosphate

glucose

Glycolysis:

Glycogen

Glucose-1-phosphate

Glucose-6-phosphate

glucose

EpinephrineEpinephrine

Glycogen phosphorylase

1. When epinephrine was added to a Test-tube mixture containing the phosphorylase and its substrate, glycogen

no depolymerization occurred

2. Epinephrine could activate glycogen phosphorylase

only when it was added to a solution containing intact cells.

Enzyme:

1. Epinephrine does not interact directly with the enzyme responsible for glycogen breakdown.

2. The plasma membrane is somehow involved in transmitting the epinephrine signal.

Relay molecules 1.1. Catalysis by an Catalysis by an enzymeenzyme

2.2. Rearrangement of the Rearrangement of the cytoskeletoncytoskeleton

3.3. Activation of specific Activation of specific genes in the nucleusgenes in the nucleus

Signal reception and the initiation of

transduction yeast cell only “heard” the signals by its prospective mates, a cells.

The signal receptor is the identity tag on the target cell.

A signal molecule binds to a receptor protein, causing the protein to change shape.

receptor

ligand* The term for a small molecule that specifically binds to a larger one

receptor

Conformational change

activation

Key & lock

Most signal receptors are Most signal receptors are plasma membrane plasma membrane

proteinsproteins

Receptor transmits information from the extracellular Receptor transmits information from the extracellular environment to the inside of the cell by environment to the inside of the cell by changing shapchanging shapee or or aggregatingaggregating when a specific ligand binds to it. when a specific ligand binds to it.

Three major types of membrane receptors:Three major types of membrane receptors:

1.1. G-protein-linked receptorsG-protein-linked receptors 2. tyrosin-kinase receptors2. tyrosin-kinase receptors 3. ion-channel receptors3. ion-channel receptors

1.1. G-protein-linked receptorsG-protein-linked receptors --- a plasma membrane receptor--- a plasma membrane receptor

--- works with the help of a protein called a --- works with the help of a protein called a G G

proteinprotein

--- vary in their --- vary in their binding sites for recognizing signal binding sites for recognizing signal

moleculesmolecules and for recognizing and for recognizing different G different G

proteinsproteins

Figure 11.7

Figure 11.7

Cellular response

GDPGTP

P i

G-protein-linkedReceptor

Plasma Membrane

EnzymeG-protein(inactive)CYTOPLASM

Cellular response

Activatedenzyme

ActivatedReceptor

Signal molecule Inctivateenzyme

GDP

GDP

GTP

GTP

P i

GDP

Segment thatinteracts withG proteins

Signal-binding site

G protein: GDP bound --- inactive

GTP bound --- active

G-protein-linked receptor:

--- widespread and diverse in functions. * mouse embryogenesis * sensory reception (vision and smell) 視覺 嗅覺

--- involved in diseases. cholera 霍亂 pertussis 百日咳

1. 2.

3. 4.

Signalmolecule

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

PP

P

P Tyr

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

2. Tyrosine-Kinase Receptors

--- a type of receptor specialized for triggering more

than one signal-transduction pathway at once.

( have enzymatic activity 酵素活性 : tyrosin kinase)

1.1. Polypeptide aggregationPolypeptide aggregation

2.2. Phosphorylation of the Phosphorylation of the

receptorreceptor

The ability of a single ligand-binding event to trigger so many pathways is a key difference between these receptors and G-protein-linked receptors.

Ligand independent activation of tyrosin-kinase receptor

Mutation ( 突變 )

Ion-channel receptors:

Ligand-gated ion channels

* Nervous system

Cellularresponse

Gate open

Gate close

Ligand-gatedion channel receptor

Plasma Membrane

Signalmolecule(ligand)

Figure 11.7

Gate closed Ions

Not all signal receptors are membrane proteins !!

Intracellular receptorsIntracellular receptors : :

--- in the cytosol or nucleus of target cells.--- in the cytosol or nucleus of target cells.

--- --- * hydrophobic* hydrophobic : steroid hormones : steroid hormones tyroid hormonestyroid hormones

ex. Testosterone (one steroid hormone)ex. Testosterone (one steroid hormone) --- secreted from testis--- secreted from testis

* small molecules : nitric oxide (NO)* small molecules : nitric oxide (NO)

transcription

translation

Activated testosterone receptor

Transcription factors

In nucleus:

ex, estrogen receptors

Relay molecules 1.1. Catalysis by an Catalysis by an

enzymeenzyme

2.2. Rearrangement of the Rearrangement of the

cytoskeletoncytoskeleton

3.3. Activation of specific Activation of specific

genes in the nucleusgenes in the nucleus

Signal-transduction pathways

--- multistep pathway--- signal amplification

Protein phosphorylation Conformational change

Protein phosphorylation:Protein phosphorylation:

--- a widespread cellular mechanism for regulating protein activity.

Protein kinase: (Protein kinase: ( 磷酸激酶磷酸激酶 )) - - an enzyme that transfers phosphatean enzyme that transfers phosphate groups from ATP to a protein.groups from ATP to a protein.

AA AA Pkinase

phosphatase

ATP ADP

P i

inactive active

Protein phosphatase: (Protein phosphatase: ( 去磷酸酶去磷酸酶 )) - - an enzyme that remove phosphatean enzyme that remove phosphate groups from proteins.groups from proteins.

A phosphorylation cascade

Protein kinase: tyrosin kinase serine/threonine kinase

1%

Not all components of signal-transduction pathway are proteins !!

Many signaling pathways also involve small, nonprotein, water-soluble molecules or ions

Second messengers

* Spread by “diffusion”* Participate in pathways initiated by both G-protein-linked receptors and tyrosin-kinase receptors.* Including cyclic AMP and calcium ions (Ca2+).

Cyclic AMPCyclic AMP

Cyclic adenosine monophosphate; cyclic AMP; cAMPCyclic adenosine monophosphate; cyclic AMP; cAMP

Figure 11.9

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

HOAdenylyl cyclase Phoshodiesterase

Pyrophosphate

Cyclic AMP AMPOH OH

O

i

• Many G-proteins– Trigger the formation of cAMP, which then acts as a sec

ond 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

* Some are inhibitory G protein which inhibit adenylyl cyclase.

* Cholera --- Vibrio cholerae --- produce a toxin, which modifies a G protein involved in regulating salt and water secretion.

Neurotransmitters

Growth factors

hormones

Cytosolic concentrationCytosolic concentration

of of calcium ions (Cacalcium ions (Ca2+)2+)

Ca2+

More widely used

than cAMP as a

second messenger

Muscle cell contraction

secretion

Cell division

Ca2+ concentration in the cytosol is normally much

lower than the concentration outside the cell.

10,000X

* Diacylglycerol (DAG)* Inositol trisphosphate

(IP3)

EXTRACELLULARFLUID

Plasmamembrane

ATP

CYTOSOL

ATP Ca2+

pump

Ca2+

pump

Ca2+

pump

Endoplasmicreticulum (ER)

Nucleus

Mitochondrion

Key High [Ca2+] Low [Ca2+]

Figure 11.11

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 CPIP2

IP3

(second messenger)

DAG

Cellularresponse

GTP

Ca2+

(second messenger)

Ca2+

IP3-gatedcalcium channel

* Calcium and IP* Calcium and IP33 in signaling pathways. in signaling pathways.

Concept 11.4Concept 11.4

Response:Response: cell signaling leads to cell signaling leads to regulation of cytoplasmic actiregulation of cytoplasmic activitiesvities or or transcription transcription

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)

ATPCyclic 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

ReceptionReception

Transduction

Response

mRNANUCLEUS

Gene

P

Activetranscriptionfactor

Inactivetranscriptionfactor

DNA

Phosphorylationcascade

CYTOPLASM

Receptor

Growth factor

cytoplasmic recytoplasmic responsesponse

nucleus rnucleus responseesponse

Why are there often so many steps between a signaling event at the cell surface and the cell’s response ?

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)

ATPCyclic 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

Two important benefits:Two important benefits:

1.1. Signal amplificationSignal amplification

2.2. The specificity of responseThe specificity of response

* At each catalytic step in the cascade, the number of activated products is much greater than in the preceding step.

Signaling pathways with a multiplicity of steps have

two important benefits:

1. amplify the signal

2. contribute to the specificity of response

The specificity of cell signaling

epinephrineepinephrine

Liver cell heart cell

Glycogen breakdown contraction

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

Response 1

Response 4 Response 5

Response

2

Response

3

Signalmolecule

Activationor inhibition

Receptor

Relaymolecules

Figure 11.15

The response of a particular cell to a signal depends on its The response of a particular cell to a signal depends on its particular collection of signal receptor proteins, relay protparticular collection of signal receptor proteins, relay proteins, and proteins needed to carry out the responseeins, and proteins needed to carry out the response..

• Scaffolding proteins

– Can increase the signal transduction efficiency

Signalmolecule

Receptor

Scaffoldingprotein

Threedifferentproteinkinases

Plasmamembrane

Figure 11.16

Signaling Efficiency: Scaffolding Proteins and Signaling Efficiency: Scaffolding Proteins and Signaling ComplexesSignaling Complexes

• Signal response is terminated quickly– By the reversal of ligand binding– The relay molecules return to their inactive forms.

Termination of the SignalTermination of the Signal

How ?How ?

A key to a cell’s continuing receptiveness to

regulation is the reversibility of the changes that

signals produce.