Cell Cell Communication-ICommunication-I

Pin Ling ( 凌 斌 ), Ph.D.

Department of Microbiology & Immunology, NCKU

ext 5632; lingpin@mail.ncku.edu.tw

Reference:

“Mechanisms of Cell Communication”, The Cell (5th edition), Chapter 15

Outline General principles of cell communication

Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators

Signaling through enzyme-coupled cell-surface receptors

Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins

Signaling in plants

Your involvement is the key to success in this lecture.

Features of Cell CommunicationFeatures of Cell Communication

1. A single host cell (E. Coli) or multicellular organisms need to communicate with environmental cues (stimuli), then leading to appropriate responses.

2. How to do “Communication” with environmental cues?=> Signaling Transduction

What is Signaling Transduction?What is Signaling Transduction?

• Conversion of a signal from one physical or chemical form into another.

• The process initiated by recognition a Signal by a Sensor (receptor, kinase or enzyme) in the cell, then converting to one or more cellular responses through a series of signal

transmission.

Inputs

Responses

Signals

Cellular Responses (Proliferation, Differentiation, & Apoptosis)

Signaling Cascades Cell

Signaling Transduction Regulates Cellular Responses

Human

ReceptorsReceptors

Signal Signal TransduceTransduce

rsrs

EffectorsEffectors

A simple scheme of signal A simple scheme of signal transductiontransduction

Molecules involved in this process,

called Signaling Molecules

Figure 15-2 Molecular Biology of the Cell (© Garland Science 2008)

Budding yeast cells responding Budding yeast cells responding to to a mating factor (Pheromone)a mating factor (Pheromone)

Budding yeast

Features of Cell Features of Cell Communication-ICommunication-I

1. Signal molecules bind to surface or intracellular receptors.

2. There are four types of cellular signaling: (1) Cell contact, (2) Paracrine, (3) Synaptic, and (4) Endocrine.

3. Extracellular signal molecules can act over short or

long distance.

4. Extracellular signals can act slowly or rapidly to change the behavior of a target cell.

Cell surface vs intracellular Cell surface vs intracellular receptorsreceptors

Four types of intercellular Four types of intercellular signalingsignaling

Signaling via gap junctions Signaling via gap junctions

Strategies for long-range Strategies for long-range signalingsignaling

Early vs later responses to Early vs later responses to extracellular signals extracellular signals

Features of Cell Features of Cell Communication-IICommunication-II

1. Each cell is programmed to respond to the combinations of extracellular signal molecules.

2. Different cell types respond differently to the same extracellular signal molecules.

3. The same cell type can act differently depending upon signal concentration.

4. Examples of intracellular signaling, e.g. NO signaling, Nuclear receptor signaling.

Combinations of total Combinations of total signals decide the cell fatesignals decide the cell fate

Various cellular Various cellular responses induced by responses induced by

acetylcholineacetylcholine

The same cell type can act The same cell type can act differently upon signal differently upon signal

concentrationconcentration

NO functions in smooth NO functions in smooth muscle relaxationmuscle relaxation

Steroid hormones & other Steroid hormones & other non-gaseous signal non-gaseous signal

molecules molecules

The Nuclear Receptor FamilyThe Nuclear Receptor Family

Activation of nuclear Activation of nuclear receptors by ligand bindingreceptors by ligand binding

Primary & secondary Primary & secondary responses by nuclear responses by nuclear

receptorsreceptors

Outline General principles of cell communication

Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators

Signaling through enzyme-coupled cell-surface receptors

Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins

Signaling in plants

Three classes of cell surface Three classes of cell surface receptorsreceptors

Three classes of cell surface Three classes of cell surface receptorsreceptors

Features of intracellular Features of intracellular signaling pathways-I signaling pathways-I

1. Small intracellular signaling molecules => 2nd messengers, e.g. Ca2+, cAMP, or Diacylglycerol (DAG).

2. Large intracellular signaling molecules => Signaling proteins

3. Signaling proteins act as “Molecular Switches” regulated by post-translational modifications (PTMs).

4. Signaling complex formation enhances the efficiency & specificity of the response.

5. Modular interaction domains mediate interactions between signaling proteins

A A Signaling Signaling cascade: A cascade: A surface surface receptor to receptor to the the nucleusnucleus

Molecular Switches: Molecular Switches:

Post-Translational Post-Translational ModificationsModifications

Signal IntegrationSignal Integration

Signaling complex formation Signaling complex formation by a scaffold proteinby a scaffold protein

Signaling complex formation Signaling complex formation by by

an activated receptoran activated receptor

Signaling complex formation Signaling complex formation on phosphoinositoide on phosphoinositoide

docking sites docking sites

Signaling complex formation Signaling complex formation usingusing

modular interaction domains modular interaction domains

Features of intracellular Features of intracellular signaling pathways-II signaling pathways-II

1. Cells can respond abruptly or gradually to an increasing signal.

2. Intracellular signaling networks use feedback loops to regulate the process.

3. Cells can adjust their sensitivity to a signal.

Smoothly graded vs Smoothly graded vs switchlike signaling switchlike signaling

responses-Iresponses-I

Smoothly graded vs Smoothly graded vs switchlike signaling switchlike signaling

responses-IIresponses-II

Activation curves for an allosteric Activation curves for an allosteric protein by various effector protein by various effector concentrationsconcentrations

A positive vs negative A positive vs negative feedback loopfeedback loop

Positive vs negative Positive vs negative feedback loopfeedback loop

An example of An example of a positive a positive feedback loopfeedback loop

Many ways to become Many ways to become desensitized (adapted) to a desensitized (adapted) to a

signalsignal

Outline General principles of cell communication

Signaling through G-protein-coupled cell surface receptors (GPCRs) and small intracellular mediators

Signaling through enzyme-coupled cell-surface receptors

Signaling pathways dependent on regulated proteolysis of latent gene regulatory proteins

Signaling in plants

Signaling through G-protein-Signaling through G-protein-coupled cell surface receptors coupled cell surface receptors

(GPCRs)-I(GPCRs)-I1. GPCRs are the largest family of cell-surface

receptors (700 GRCRs in human). They mediate our sense of sight, smell, and taste.

2. Extracellular signaling molecules acting on GPCRs are varied in structure, including hormones, lipid mediators, & neurotransmitters.

3. All GPCRs have a common structure- a seven transmembrane peptide

4. All GPCRs use G proteins to relay the signal into the cell.

Signaling through G-protein-Signaling through G-protein-coupled cell surface receptors coupled cell surface receptors

(GPCRs)-II(GPCRs)-II5. Some G proteins regulate the production of

cyclic AMP.

6. Some G proteins activate an inosital phospholipid signaling pathway via Phospholipase C-beta (PLC-b).

GPCRs and G ProteinGPCRs and G Protein

GPCR

G Protein: subunit: GTPase subunit & subunit

Activation of Activation of GPCRs & GPCRs &

G ProteinG Protein

cAMP links some GPCR cAMP links some GPCR signals to gene expressionsignals to gene expression

Some hormones act GPCR Some hormones act GPCR via cAMPvia cAMP

Activation of cAMP-dep Activation of cAMP-dep protein kinase (PKA)protein kinase (PKA)

Some GPCRs activate PKC Some GPCRs activate PKC and cytosolic Caand cytosolic Ca2+2+

CaCa2+2+-mediated intracellular -mediated intracellular SignalingSignaling

1. Ca2+ functions as an intracellular mediator.

2. Ca2+ enter the cytosol from outside through various Ca2+ ion channel.

3. Ca2+ from the ER enter the cytosol through IP3

receptors or ryanodine receptors.

4. Several mechanisms keep Ca2+ in the cytosol low in resting cells.

5. Ca2+ oscillations affect a cell response.

6. Ca2+/Calmodulin-dep protein kinase mediate cellular responses (learning & memory in the nervous system).

Ca2+ functions as an Ca2+ functions as an intracellular mediatorintracellular mediator

Multiple ways to keep Ca2+ Multiple ways to keep Ca2+ low in the cytosollow in the cytosol

Vasopressin-induced Ca2+ Vasopressin-induced Ca2+ oscillations in a liver celloscillations in a liver cell

Vasopressin

GPCR

PLC-

Ca2+ oscillations

Activation of CaM-kinase IIActivation of CaM-kinase II

CaM-kinase II as a CaM-kinase II as a frequency decoder of Ca2+ frequency decoder of Ca2+

oscillationsoscillations

Smell &vision depend on Smell &vision depend on GPCRsGPCRs

A rod photoreceptor cell & A rod photoreceptor cell & its response to lightits response to light

A rod A rod photoreceptor photoreceptor cell & its cell & its response response

to lightto light

Four major families of Four major families of trimeric G proteinstrimeric G proteins

GPCR desensitization GPCR desensitization depends on receptor depends on receptor

phosphorylationphosphorylation

““Cell Communication Cell Communication II” to be continuedII” to be continued

Figure 15-47 Molecular Biology of the Cell (© Garland Science 2008)