Cell-to-cell communication Signal pathways Novel signal molecules Modulation of signal pathways Control pathways Response loops Feedback loops

(1)

Chapter 6a

Communication,

Integration,

(2)

About this Chapter

• Cell-to-cell communication

• Signal pathways

• Novel signal molecules

• Modulation of signal pathways

• Control pathways

• Response loops

(3)

Cell-to-Cell Communication: Overview

• Physiological signals

• Electrical

signals

• Changes in the membrane potential of a cell

• Chemical

signals

• Secreted by cells into ECF

• Responsible for most communication within the

body

• Target cells, or targets, receive signals

(4)

Figure 6-1a

Cell-to-Cell Communication: Methods

• Direct contact and

local cell-to-cell

communication

• Gap junctions

• Transfer both

chemical and

electrical signals

• Form direct

cytoplasmic

connections between

adjacent cells.

• Protein connexins

(5)

Cell-to-Cell Communication: Methods

• CAMs

, cell adhesion

molecules, transfer

signals in both

directions

• Common in Immune

system

• Contact-dependent

signals

require

(6)

Cell-to-Cell Communication: Methods

• Direct contact and local cell-to-cell

communication

• Autocrine signals

act on the same cell that

secreted them.

Paracrine signals

are

secreted by one cell and diffuse to adjacent

cells.

Figure 6-1c

(c) Autocrine signals and paracrine

signals

(7)

Cell-to-Cell Communication: Methods

• Paracrine

and

autocrine

are chemical

signals

• Hormones are secreted by endocrine glands

or cells into the blood. Only target cells with

receptors for the hormone will respond to the

signal.

Endocrine

cell

Cell

without

receptor

Cell

with

receptor

No response

(8)

Cell-to-Cell Communication: Methods

• Long distance cell-to-cell communication

• Neurotransmitters are chemicals secreted by

neurons that diffuse across a small gap to the

target cell. Neurons use electrical signals as

well.

• Neurotransmitters have a rapid effect

Figure 6-2b

(b) Neurotransmitters

Neuron

Electrica

l

signal

Target

(9)

Cell-to-Cell Communication: Methods

• Neurohormones are chemicals released by

neurons into the blood for action at distant

targets.

Cell

without

receptor

Cell

with

receptor

No response

(c)

Neurohormones

Neuron

(10)

Cell-to-Cell Communication: Methods

• Cytokines

may act as both local and

long-distance signals

• All nucleated cells synthesize and secrete

cytokines in response to stimuli

• In development and differentiation, cytokines

usually function as autocrine or paracrine

signals

• In stress and inflammation, some cytokines

(11)

Signal Pathways: Overview

Receptor

protein

Intracellular

signal

molecules

Signal

molecule

Target

proteins

Response

binds to

activate s

alter s

(12)

Signal Pathways: Receptor locations

• Target cell receptors

• Lipophilic vs lipophobic

Figure 6-4 (1 of 2)

Slower responses

related to changes

in gene activity

Receptor

in cytosol

Recepto

r

in nucleus

Lipophilic

signal

molecules

(13)

Signal Pathways: Receptor locations

Lipophobic signal

molecule

Recepto

r

Ligand-receptor complex

Rapid cellular

responses

Extracellular

fluid

Intracellular fluid

(14)

Signal Pathways: Membrane Receptors

• Four categories of membrane receptors

Figure 6-5

Cell membran

e

ECF

ICF

G protein Recepto

r Channe

l

Extracellula r signal molecules

Integrin Recepto

r

Enzym e

Anchor protein

Cytoskeleto n

Receptor -channel

Receptor-enzym e

Integrin receptor G protein-coupled

receptor

Signal molecul e Recepto r

Intracellula r

(15)

Signal Transduction

Radio

waves

Recepto

r

Transduce

r

Amplifie

r

Respons

External

signal

(16)

Signal Pathways: Signal Amplification

• Transducers

convert extracellular signals

into intracellular messages which create a

response

Figure 6-7

Extracellula

r

fluid

Intracellula

r

fluid

Cell

membran

e

Receptor-ligand complex

activates an

amplifier enzyme (AE).

Signal molecul e

Recepto r

Intracellula r

(17)

(18)

Signal Pathway: Biological Signal Transduction

• Biological

signal

transduction

converts

chemical

signals into

cellular

responses

Figure 6-8

alte r Signal molecul e Membrane receptor Signal transduction by proteins Amplifier enzymes Second messenger molecules Protein kinases Increase intracellular Ca2+

Phosphorylate d proteins Calcium-binding proteins Extracellula r fluid Intracellula r fluid Cell response initiate s binds to

(19)

Signal Pathway: Signal Transduction

• Steps of signal transduction pathway form a

cascade

Inactive

A

Inactive

B

Inactive

C

Substrat

Active

A

Active

B

Active

C

Initial

stimulu

(20)

Signal Pathway: Receptor Enzymes

• Tyrosine kinase, an example of

receptor-enzyme

Figure 6-10

+

Protein

Active binding

site

+ ADP

ECF

IC

F

Signal molecule binds

to surface receptor

Phosphorylate

d

protein

Tyrosine kinase

on

cytoplasmic side

Cell

membrane

activates

Protei

n

Signal molecul e

Recepto r

Intracellula r

signal molecules

(21)

Signal Pathway: GPCR

• Membrane-spanning proteins

• Cytoplasmic tail linked to G protein, a

three-part transducer molecule

• When G proteins are activated, they

• Open ion channels in the membrane

• Alter enzyme activity on the cytoplasmic side of

(22)

GPCR: Adenylyl Cyclase-cAMP

Figure 6-11

1

One signal

molecule Adenylyl cyclase

ATP

cAMP G

protein

Protein kinase A

Phosphorylated protein

Cell response

Signal molecule binds to G protein-linked receptor, which activates the G protein.

Protein kinase A phosphorylates other proteins, leading

ultimately

to a cellular response. G protein turns on adenylyl cyclase, an amplifier enzyme.

Adenylyl cyclase converts ATP to cyclic AMP.

cAMP activates protein

kinase A. 2

3

4

5

1

2

3

4

(23)

GPCR: Adenylyl Cyclase-cAMP

1

One signal molecule

G protein

(24)

GPCR: Adenylyl Cyclase-cAMP

Figure 6-11, steps 1–2

1

One signal

G protein

G protein turns on adenylyl cyclase, an amplifier enzyme.

2

1

(25)

GPCR: Adenylyl Cyclase-cAMP

1

One signal

ATP

cAMP G

protein

2

3

1

2

(26)

GPCR: Adenylyl Cyclase-cAMP

Figure 6-11, steps 1–4

1

One signal

ATP

cAMP G

protein

kinase A. 2

3

4

1

2

3

(27)

GPCR: Adenylyl Cyclase-cAMP

1

One signal

ATP

cAMP G

protein

Phosphorylated protein

Cell response

Protein kinase A phosphorylates other proteins, leading

ultimately

to a cellular response. G protein turns on adenylyl cyclase, an amplifier enzyme.

kinase A. 2

3

4

5

1

2

3

4

(28)

GPCR: The Phospholipase C System

Figure 6-12

1

Membrane phospholipid

Protein + P_i

Cell membran e Extracellula r fluid Intracellula r fluid DAG Phosphorylate d protein PL-C DAG PK-C IP₃ E R = = = = = phospholipase C diacylglycero lprotein kinase C inositol trisphosphate endoplasmic reticulum E R Recepto r G protein Cellula r respons e Signal molecul e Signal molecule activates receptor and associated G protein.

G protein activates phospholipase C (PL-C), an amplifier enzyme.

PL-C converts membrane phospholipids into diacylglycerol (DAG) which

remains in the membrane, and IP₃, which diffuses into the cytoplasm.

DAG activates protein kinase C (PK-C), which

phosphorylates proteins.

IP₃ causes release of Ca2+_from

organelles, creating a Ca2+_signal.

KEY PL-C

IP

3

PK-C

Ca2+_stores _Ca2+

2 3 ₄

5

(29)

GPCR: The Phospholipase C System

1

Cell membran

e

Extracellula r fluid

Intracellula r fluid

PL-C DAG PK-C IP₃ E R

= = = = =

phospholipase C

diacylglycero lprotein kinase C

inositol trisphosphate endoplasmic reticulum Recepto

r G

protein Signal

molecul e

Signal molecule activates receptor and associated G protein.

KEY

(30)

GPCR: The Phospholipase C System

Figure 6-12, steps 1–2

1 Cell membran e Extracellula r fluid Intracellula r fluid PL-C DAG PK-C IP₃ E R = = = = = phospholipase C diacylglycero lprotein kinase C inositol trisphosphate endoplasmic reticulum Recepto r G protein Signal molecul e Signal molecule activates receptor and associated G protein.

KEY PL-C

2

(31)

GPCR: The Phospholipase C System

1 Membrane phospholipid Cell membran e Extracellula r fluid Intracellula r fluid DAG PL-C DAG PK-C IP₃ E R = = = = = phospholipase C diacylglycero lprotein kinase C inositol trisphosphate endoplasmic reticulum Recepto r G protein Signal molecul e Signal molecule activates receptor and associated G protein.

KEY PL-C

IP

3

2 3

(32)

GPCR: The Phospholipase C System

Figure 6-12, steps 1–4

1

Protein + P_i

Cell membran e Extracellula r fluid Intracellula r fluid DAG Phosphorylate d protein PL-C DAG PK-C IP₃ E R = = = = = phospholipase C diacylglycero lprotein kinase C inositol trisphosphate endoplasmic reticulum Recepto r G protein Cellula r respons e Signal molecul e Signal molecule activates receptor and associated G protein.

DAG activates protein kinase C (PK-C), which phosphorylates proteins. KEY PL-C IP 3 PK-C

2 3 ₄

(33)

GPCR: The Phospholipase C System

1

Protein + P_i

Cell membran e Extracellula r fluid Intracellula r fluid DAG Phosphorylate d protein PL-C DAG PK-C IP₃ E R = = = = = phospholipase C diacylglycero lprotein kinase C inositol trisphosphate endoplasmic reticulum E R Recepto r G protein Cellula r respons e Signal molecul e Signal molecule activates receptor and associated G protein.

DAG activates protein kinase C (PK-C), which

phosphorylates proteins.

IP₃ causes release of Ca2+_from

organelles, creating a Ca2+_signal.

KEY PL-C

IP

3

PK-C

Ca2+_stores

Ca2+

2 3 ₄

5

(34)

Signal Pathway: Receptor-Channel

• Some second messengers create electrical

signals

Figure 6-13

1

Receptor-channels open or close in response to signal molecule binding.

Some channels are directly linked to G proteins.

Other ligand-gated channels respond to intracellular second messengers. Extracellular

signal molecules

Ions

Ion channel

G protein

Change in membrane permeability to

Na+_{, K}+_{, Cl}–

Creates electrical signal

Voltage-sensitive protein

Cellular response

G protein-coupled receptor

Intracellular signal molecules 2

3

2

(35)

Signal Pathway: Receptor-Channel

1

Extracellula r signal molecules

Ions

Ion channel

(36)

Signal Pathway: Receptor-Channel

Figure 6-13, steps 1–2

1

Some channels are directly

linked to G proteins. Extracellula

r signal molecules

Ions

Ion channel

G protein

2

(37)

Signal Pathway: Receptor-Channel

1

linked to G proteins.

Other ligand-gated channels

respond to intracellular Extracellula

r signal molecules

Ions

Ion channel

G protein

Intracellular signal molecules

2

3

2

(38)

Signal Pathway: Receptor-Channel

Figure 6-13

1

linked to G proteins.

Other ligand-gated channels

respond to intracellular second messengers. Extracellula r signal molecules Ions Ion channel G protein

Change in membrane permeability to

Na+_{, K}+_{, Cl}–

(39)

Signal Pathway: Signal Transduction

• Summary map of signal transduction systems

Ion s Gated ion channel alters alter create s produce s activate phosphorylat e

will be a change in

phosphorylate s Extracellular fluid Intracellular fluid Cell membrane Protein kinases Altered proteins Change in ion concentratio n Electrical signal Ions move into or out of cell

Membrane _{Gene activity}

Activates or inhibits amplifier enzyme Second messenger molecules Triggers release of Ca2+_from