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.

(5)

Cell-to-Cell Communication: Methods

• CAMs

, cell adhesion

molecules, transfer

signals in both

directions

• Common in Immune

system

• Contact-dependent

signals

require

interaction between

membrane

(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

Electrical

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

activates

alters

(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

Receptor

in nucleus

Lipophilic signal

molecules

(13)

Signal Pathways: Receptor locations

Lipophobic signal molecule

Receptor

Ligand-receptor complex

Rapid cellular

responses

Extracellular

fluid

Intracellular fluid

(14)

Signal Pathways: Membrane Receptors

• Four categories of membrane receptors

Figure 6-5

Cell membrane

ECF

ICF

G protein Receptor Channel

Extracellular signal molecules

Integrin Receptor

Enzyme

Anchor protein

Cytoskeleton

Receptor-channel Receptor-enzyme G protein-coupled receptor Integrin receptor

Signal molecule

(15)

Signal Transduction

Radio Radio waves

Receptor

Transducer

Amplifier

Response External

signal

(16)

Signal Pathways: Signal Amplification

• Transducers

convert extracellular signals

into intracellular messages which create a

response

Figure 6-7

Extracellular fluid

Intracellular fluid

Receptor-ligand complex activates an

amplifier enzyme (AE).

(17)

(18)

Signal Pathway: Biological Signal Transduction

• Biological

signal

transduction

converts

chemical

signals into

cellular

responses

Figure 6-8

alter Signal molecule Membrane receptor Signal transduction by proteins Amplifier enzymes Second messenger molecules

Protein kinases _{intracellular Ca}Increase ₂₊

Phosphorylated

proteins Calcium-bindingproteins

Extracellular fluid Intracellular fluid Cell response initiates

binds to

(19)

Signal Pathway: Signal Transduction

• Steps of signal transduction pathway form a

cascade

Inactive A

Inactive B

Inactive C

Substrate

Active A

Active B

Active C

(20)

Signal Pathway: Receptor Enzymes

• Tyrosine kinase, an example of

receptor-enzyme

Figure 6-10

+ Protein

Active binding site

+ ADP

ECF

ICF

Signal molecule binds

to surface receptor

Phosphorylated

protein

Tyrosine kinase on

cytoplasmic side

Cell

membrane

activates

Protein

Receptor

Intracellular 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.

(23)

GPCR: Adenylyl Cyclase-cAMP

1

One signal molecule

G protein

(24)

GPCR: Adenylyl Cyclase-cAMP

Figure 6-11, steps 1–2

1

Adenylyl cyclase

G protein

2

1

(25)

GPCR: Adenylyl Cyclase-cAMP

1

ATP

cAMP G protein

2

3

1

2

(26)

GPCR: Adenylyl Cyclase-cAMP

Figure 6-11, steps 1–4

1

ATP

Protein kinase A

cAMP activates protein kinase A.

2

3

4

1

2

3

(27)

GPCR: Adenylyl Cyclase-cAMP

1

ATP

Protein kinase A

Phosphorylated protein

Cell response

Protein kinase A phosphorylates other proteins, leading ultimately to a cellular response.

cAMP activates protein 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 membrane Extracellular fluid Intracellular fluid DAG Phosphorylated protein PL-C DAG PK-C IP₃ ER = = = = = phospholipase C diacylglycerol protein kinase C inositol trisphosphate endoplasmic reticulum ER Receptor G protein Cellular response Signal molecule 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

IP₃

PK-C

Ca2+_stores _Ca2+

2 3 ₄

5

(29)

GPCR: The Phospholipase C System

1

Extracellular fluid

Intracellular fluid

PL-C DAG PK-C IP₃ ER

= = = = =

phospholipase C diacylglycerol protein kinase C inositol trisphosphate endoplasmic reticulum Receptor

G protein Signal

molecule

Signal molecule activates receptor and associated G protein.

KEY

(30)

GPCR: The Phospholipase C System

Figure 6-12, steps 1–2

1 Cell membrane Extracellular fluid Intracellular fluid PL-C DAG PK-C IP₃ ER = = = = = phospholipase C diacylglycerol protein kinase C inositol trisphosphate endoplasmic reticulum Receptor G protein Signal molecule Signal molecule activates receptor and associated G protein.

KEY

PL-C

2

(31)

GPCR: The Phospholipase C System

1 Membrane phospholipid Cell membrane Extracellular fluid Intracellular fluid DAG PL-C DAG PK-C IP₃ ER = = = = = phospholipase C diacylglycerol protein kinase C inositol trisphosphate endoplasmic reticulum Receptor G protein Signal molecule Signal molecule activates receptor and associated G protein.

KEY

PL-C

IP₃

2 3

(32)

GPCR: The Phospholipase C System

Figure 6-12, steps 1–4

1

Protein + P_i

Cell membrane Extracellular fluid Intracellular fluid DAG Phosphorylated protein PL-C DAG PK-C IP₃ ER = = = = = phospholipase C diacylglycerol protein kinase C inositol trisphosphate endoplasmic reticulum Receptor G protein Cellular response Signal molecule Signal molecule activates receptor and associated G protein.

DAG activates protein kinase C (PK-C), which phosphorylates proteins. KEY PL-C IP₃ PK-C

2 3 ₄

(33)

GPCR: The Phospholipase C System

1

Protein + P_i

Cell membrane Extracellular fluid Intracellular fluid DAG Phosphorylated protein PL-C DAG PK-C IP₃ ER = = = = = phospholipase C diacylglycerol protein kinase C inositol trisphosphate endoplasmic reticulum ER Receptor G protein Cellular response Signal molecule 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

IP₃

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}–

(35)

Signal Pathway: Receptor-Channel

1

Ions

Ion channel

(36)

Signal Pathway: Receptor-Channel

Figure 6-13, steps 1–2

1

Some channels are directly linked to G proteins.

Ions

Ion channel

G protein

G protein-coupled receptor 2

(37)

Signal Pathway: Receptor-Channel

1

Other ligand-gated channels respond to intracellular Extracellular

signal molecules

Ions

Ion channel

G protein

G protein-coupled receptor

Intracellular signal molecules 2

3

2

(38)

Signal Pathway: Receptor-Channel

Figure 6-13

1

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}–

(39)

Signal Pathway: Signal Transduction

• Summary map of signal transduction systems

Ions Gated ion channel alters alter creates produces activate phosphorylate

will be a change in

phosphorylates Extracellular fluid Intracellular fluid Cell membrane Protein kinases Altered proteins Change in ion

concentration