Signalling pathways induced in cells
How to define cell signal
Signalling
Electrical Signals- changes in cell’s membrane potential
Chemical Signals- molecules secreted by cells into extracellular fluid
o Responsible for most communication within body
Cells that respond to electrical/ chemical signalling- Target cells/ Targets
(Bio)chemical Signalling
For biochemical signals- LIGAND and RECEPTOR needed
Chemical signal acts as LIGANDS – bind to proteins to initiate response
- Protein binding of chemical signals obeys general rules for protein interactions- Specificity, Affinity,
Competition and Saturation
Signal LIGAND- small molecule that forms complex with macromolecule- RECEPTOR- protein that results in
conformational change in receptor- generates signal
Chemical signal molecules are secreted by cells into extracellular compartment
A cell can respond to particular chemical signal only if cell has appropriate receptor protein to bind that signal
All signal pathways share same features:
1) Signal Molecule- Ligand- binds to receptor protein
a. Also known as First messenger- brings information to target cell
2) Ligand-receptor binding- activates receptor
3) Receptor activates one/more intracellular signal molecules
4) Last signal molecule in pathway- creates response by modifying existing proteins/ initiating synthesis of
new proteins
Forms of signal- Where is signal released from?
Contact- dependent signals (Juxtacrine)- signals target
adjacent touching cells
Cell- Matrix signals- signals from insoluble extracellular matrix
Soluble Signals- AUTOCRINE (intracrine), PARACRINE and ENDOCRINE
Local Communication includes:
1. Gap Junctions- allow direct cytoplasmic transfer of electrical and chemical signals between adjacent cells
2. Contact-Dependent Signals- occur when surface molecules on one cell membrane bind to surface molecules
on another cell’s membrane
3. Chemicals that diffuse through extracellular fluid to act on cells close by
4. Long- distance communication- uses combination of chemical and electrical signals carried by nerve cells
and chemical signals transported in blood
Contact- dependent signals- Juxtacrine:
Require interaction between membrane molecules on two cells (requires surface molecules on one cell
membrane bind to membrane protein of another cell)
Cells must be touching
Signals are transmitted through cell membranes- via protein/lipid components integral to membrane
emitting cells
Cell-to-cell communication uses chemical and electrical signalling- coordinate function and maintain
homeostasis
,Soluble Signals
Local-Distance communications
May be electrical signals- passing along neurons or chemical signals- travel through circulatory system
Endocrine system:
o Hormones- secreted by endocrine glands/ cells into blood. Only target cells with receptors for
hormone respond to signal
Nervous System:
o Neurotransmitters- chemicals secreted by neurones- diffuse across small gap to target cell
o Neurohormones- chemicals released by neurons into blood- action at distant targets
Gap Junctions
Protein channels- create cytoplasmic bridges between adjacent cells
o Form direct cytoplasmic connections between adjacent cells
Form union of membrane-spanning proteins- connexins- on two adjacent cells
o United connexins- create protein channel (connexon)- open and close
When channel is open- connected cells function like single cells- contains multiple nuclei
when Gap Junctions OPEN- ions and small molecules (amino acids, ATP, and cyclic AMP (cAMP) diffuse
directly from cytoplasm of one cell to cytoplasm of next
Larger molecules- can’t pass through gap junctions
Only electrical signals can pass directly from cell to cell
AUTOCRINE SIGNALS
Autocrine- signals are secreted and affect target cell itself via its own receptors
E.G.:
Interleukin-1- cytokine released by macrophages
- Effects neighbouring cells and secreting cell ‘activating them’
Interleukin-2- released by T-lymphocytes on meeting antigen and causes them to proliferate
Autocrine and Paracrine signal molecules- reach their target cells by diffusing through interstitial fluid
- Distance is limiting factor for diffusion- effective range of paracrine signals is
restricted to adjacent cells
INTRACRINE SIGNALS
Intracrine signals- produced by and stay within targeted cell
E.G.:
Steroid hormones- have their receptors in cell- can act as
intracrine
PARACRINE SIGNALS
Paracrine signals- target cells in vicinity of emitting cell
- Released by cells into extracellular fluid in their neighbourhood and act locally
E.G.:
Immune cells
Neurotransmitters at synapses
Local mediators released into interstitial fluid include- Histamine, TGFβ, Growth factors, Cytokines
Chemical Synapses- Neural signals are paracrine signals
ENDOCRINE SIGNALS
, Endocrine system communicates by using Hormones- chemical signals that are secreted into blood and distributed
all over body by circulation
Endocrine signals- target distant cells by producing hormones that travel through
circulation to reach all parts of body
E.G.:
Adrenalin
Thyroid stimulating hormone
Hormones are produced in endocrine glands- secreted into bloodstream and distributed widely throughout body
Hormones are at low concentrations in blood/ interstitial fluid
E.G. Thyroxine- 0.09-20pg/ml
Oestradiol- 20-400pg/ml
Prolactin- 3-15ng/ml 1pg= 1x10-12g
Far Lower levels (pM) than local concentration of ligands used in paracine, cell-matrix and
cell-cell signals
Hormone receptor binding has far greater affinity- low kD- compared to others
Hormone receptors are part of amplification cascades
Amplifi cati on
In signal transduction pathways- original signal is not only transformed but AMPLIFIED
Signal Amplification- turns one signal molecule into multiple second messenger molecules – allows small amount of
signal to have large effect
- Process begins when first messenger ligand combines with its receptor
- Receptor-ligand complex TURNS ON Amplification enzyme
Amplification Enzyme- activates several molecules which activates several molecules as cascade proceeds
- By the end of process- effects of ligand have been amplified
Chemical classifi cati on of External Messengers
Gases- NO, CO, H2S, CO2
o Produced by specific enzymatic pathways
o Highly soluble in water and lipids- can cross plasma membrane
o Can’t be STORED- needs to be produced on DEMAND
o Produces local- paracrine/autocrine- effects
o Cause vasodilation and may have immunological effects
CO (Carbon monoxide)- activates Guanylyl cyclase and cGMP
- Targets smooth muscle and neural tissue
H2S (Hydrogen Sulphide)- acts in cardiovascular system to relax blood vessels
Nucleic Acids- ATP, ADP and Adenosine
o Purinergic nucleotides- ATP/ADP and their nucleoside adenosine function- as paracrine signalling
molecules
o Have specific cell surface receptors- G-proteins associated
o During cellular stress- ischemia/ reperfusion or inflammation- multiple cell types release ATP into
extracellular space
o Induce vasodilation, neural effects (in development), innate immune changes- e.g. inflammatory
cytokine release, fever
Fatty acid derivatives- Eicosanoid- e.g. prostaglandins, thromboxanes, leukotrienes, PAFs
o Paracrine signals
How to define cell signal
Signalling
Electrical Signals- changes in cell’s membrane potential
Chemical Signals- molecules secreted by cells into extracellular fluid
o Responsible for most communication within body
Cells that respond to electrical/ chemical signalling- Target cells/ Targets
(Bio)chemical Signalling
For biochemical signals- LIGAND and RECEPTOR needed
Chemical signal acts as LIGANDS – bind to proteins to initiate response
- Protein binding of chemical signals obeys general rules for protein interactions- Specificity, Affinity,
Competition and Saturation
Signal LIGAND- small molecule that forms complex with macromolecule- RECEPTOR- protein that results in
conformational change in receptor- generates signal
Chemical signal molecules are secreted by cells into extracellular compartment
A cell can respond to particular chemical signal only if cell has appropriate receptor protein to bind that signal
All signal pathways share same features:
1) Signal Molecule- Ligand- binds to receptor protein
a. Also known as First messenger- brings information to target cell
2) Ligand-receptor binding- activates receptor
3) Receptor activates one/more intracellular signal molecules
4) Last signal molecule in pathway- creates response by modifying existing proteins/ initiating synthesis of
new proteins
Forms of signal- Where is signal released from?
Contact- dependent signals (Juxtacrine)- signals target
adjacent touching cells
Cell- Matrix signals- signals from insoluble extracellular matrix
Soluble Signals- AUTOCRINE (intracrine), PARACRINE and ENDOCRINE
Local Communication includes:
1. Gap Junctions- allow direct cytoplasmic transfer of electrical and chemical signals between adjacent cells
2. Contact-Dependent Signals- occur when surface molecules on one cell membrane bind to surface molecules
on another cell’s membrane
3. Chemicals that diffuse through extracellular fluid to act on cells close by
4. Long- distance communication- uses combination of chemical and electrical signals carried by nerve cells
and chemical signals transported in blood
Contact- dependent signals- Juxtacrine:
Require interaction between membrane molecules on two cells (requires surface molecules on one cell
membrane bind to membrane protein of another cell)
Cells must be touching
Signals are transmitted through cell membranes- via protein/lipid components integral to membrane
emitting cells
Cell-to-cell communication uses chemical and electrical signalling- coordinate function and maintain
homeostasis
,Soluble Signals
Local-Distance communications
May be electrical signals- passing along neurons or chemical signals- travel through circulatory system
Endocrine system:
o Hormones- secreted by endocrine glands/ cells into blood. Only target cells with receptors for
hormone respond to signal
Nervous System:
o Neurotransmitters- chemicals secreted by neurones- diffuse across small gap to target cell
o Neurohormones- chemicals released by neurons into blood- action at distant targets
Gap Junctions
Protein channels- create cytoplasmic bridges between adjacent cells
o Form direct cytoplasmic connections between adjacent cells
Form union of membrane-spanning proteins- connexins- on two adjacent cells
o United connexins- create protein channel (connexon)- open and close
When channel is open- connected cells function like single cells- contains multiple nuclei
when Gap Junctions OPEN- ions and small molecules (amino acids, ATP, and cyclic AMP (cAMP) diffuse
directly from cytoplasm of one cell to cytoplasm of next
Larger molecules- can’t pass through gap junctions
Only electrical signals can pass directly from cell to cell
AUTOCRINE SIGNALS
Autocrine- signals are secreted and affect target cell itself via its own receptors
E.G.:
Interleukin-1- cytokine released by macrophages
- Effects neighbouring cells and secreting cell ‘activating them’
Interleukin-2- released by T-lymphocytes on meeting antigen and causes them to proliferate
Autocrine and Paracrine signal molecules- reach their target cells by diffusing through interstitial fluid
- Distance is limiting factor for diffusion- effective range of paracrine signals is
restricted to adjacent cells
INTRACRINE SIGNALS
Intracrine signals- produced by and stay within targeted cell
E.G.:
Steroid hormones- have their receptors in cell- can act as
intracrine
PARACRINE SIGNALS
Paracrine signals- target cells in vicinity of emitting cell
- Released by cells into extracellular fluid in their neighbourhood and act locally
E.G.:
Immune cells
Neurotransmitters at synapses
Local mediators released into interstitial fluid include- Histamine, TGFβ, Growth factors, Cytokines
Chemical Synapses- Neural signals are paracrine signals
ENDOCRINE SIGNALS
, Endocrine system communicates by using Hormones- chemical signals that are secreted into blood and distributed
all over body by circulation
Endocrine signals- target distant cells by producing hormones that travel through
circulation to reach all parts of body
E.G.:
Adrenalin
Thyroid stimulating hormone
Hormones are produced in endocrine glands- secreted into bloodstream and distributed widely throughout body
Hormones are at low concentrations in blood/ interstitial fluid
E.G. Thyroxine- 0.09-20pg/ml
Oestradiol- 20-400pg/ml
Prolactin- 3-15ng/ml 1pg= 1x10-12g
Far Lower levels (pM) than local concentration of ligands used in paracine, cell-matrix and
cell-cell signals
Hormone receptor binding has far greater affinity- low kD- compared to others
Hormone receptors are part of amplification cascades
Amplifi cati on
In signal transduction pathways- original signal is not only transformed but AMPLIFIED
Signal Amplification- turns one signal molecule into multiple second messenger molecules – allows small amount of
signal to have large effect
- Process begins when first messenger ligand combines with its receptor
- Receptor-ligand complex TURNS ON Amplification enzyme
Amplification Enzyme- activates several molecules which activates several molecules as cascade proceeds
- By the end of process- effects of ligand have been amplified
Chemical classifi cati on of External Messengers
Gases- NO, CO, H2S, CO2
o Produced by specific enzymatic pathways
o Highly soluble in water and lipids- can cross plasma membrane
o Can’t be STORED- needs to be produced on DEMAND
o Produces local- paracrine/autocrine- effects
o Cause vasodilation and may have immunological effects
CO (Carbon monoxide)- activates Guanylyl cyclase and cGMP
- Targets smooth muscle and neural tissue
H2S (Hydrogen Sulphide)- acts in cardiovascular system to relax blood vessels
Nucleic Acids- ATP, ADP and Adenosine
o Purinergic nucleotides- ATP/ADP and their nucleoside adenosine function- as paracrine signalling
molecules
o Have specific cell surface receptors- G-proteins associated
o During cellular stress- ischemia/ reperfusion or inflammation- multiple cell types release ATP into
extracellular space
o Induce vasodilation, neural effects (in development), innate immune changes- e.g. inflammatory
cytokine release, fever
Fatty acid derivatives- Eicosanoid- e.g. prostaglandins, thromboxanes, leukotrienes, PAFs
o Paracrine signals
