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brief summary of receptors, g-protien, and 2nd messengers
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CELL SIGNALLING
By: Khuram Aziz M.phill Biochemistry
Overview of All lectures that you have learned
Its brief description and animations
Cells also communicate by direct contact.
1. Cell Junctions
Signaling substances dissolved in the cell can pass freely from one cell to another
2. Direct Contact
Through molecules on the surface of the cell
(embryonic development and the immune system)
COMMUNICATION BY DIRECT CONTACT WITH CELLS.
Local Chemical Signaling
Paracrine
Secreting cell acts on nearby target cell by discharging molecules into the extracellular fluid
Synaptic
Nerve cell releases neurotransmitter into synapses
DISTANT CELL COMMUNICATION
Hormones signal target cells at much greater distances.
Secreted into the body fluids, they reach all parts of the body.
Only specific target cells are recognized and respond
LOCAL & DISTANT CELL COMMUNICATION IN ANIMALS
Local and Distant Cell Communication In Animals.
THE THREE STAGES OF CELL SIGNALING
For a chemical signal to elicit a specific response, the target cell must possess a signaling system for the signal.
1. Reception
2. Transduction
3. Response
OVERVIEW OF CELL SIGNALING.
Reception – signal (ligand) binds to a specific cell surface protein.Transduction – binding results in conformation change of receptor. This initiates transduction (one or many steps)Response – almost any cellular activity
Many signal molecules cannot pass freely through the plasma membrane
Receptors are located on the plasma membrane
These families are called:
- G-protein linked receptors
- tyrosine kinase receptors
- ion channel receptors
Overview of the 3 Main Signal Transduction
Pathways:
e.g., neurotransmission
e.g., cAMP mediated flight or fight response (glycogen breakdown, muscle contraction)
e.g., regulation of many genes
A LIGAND-GATED ION-CHANNEL RECEPTOR.
(important in nervous system)
1. large or very polar extracellular ligand (e.g., hormone)
1. large or very polar extracellular ligand (e.g., hormone)
•changes in enzyme activity
Signal Transduction Themes:•intracellular 2nd messengers•Protein phosphorylation
3. intracellular 2nd messengers
4. protein phosphorylation
•changes in cytoskeletal organization
•changes in ion permeabilty
•activation of replication
•regulation of transcription
2. cell surface receptor2. cell surface receptor
•Membrane depolarization
STEROID HORMONES: ACTION
Figure 7-7
Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell.
Translation produces new proteins for cell processes.
Some steroid hormones also bind to mem-brane receptors that use second messenger systems to create rapid cellular responses.
Steroid hormone receptors are typically in the cytoplasm or nucleus.
The receptor-hormone complex binds to DNA and activates or represses one or more genes.
Activated genes create new mRNA that moves into the cytoplasm.
Cellmembrane
Interstitialfluid
Cytoplasmicreceptor
Endoplasmicreticulum
Nucleus
Nuclear receptor
DNA
Translation
Rapid responses
Transcriptionproduces mRNA
Steroidhormone
Bloodvessel
Proteincarrier
Newproteins
Cell surface receptor
2
3
1
4 5
2a
1
2
2a
3
45
STEROID HORMONES: ACTION
Figure 7-7, step 1
Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell.
Cellmembrane
Interstitialfluid
Nucleus
Bloodvessel
Proteincarrier
1
1
STEROID HORMONES: ACTION
Figure 7-7, steps 1–2
Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell.
Steroid hormone receptors are typically in the cytoplasm or nucleus.
Cellmembrane
Interstitialfluid
Cytoplasmicreceptor
Nucleus
Nuclear receptor
Steroidhormone
Bloodvessel
Proteincarrier2
1
1
2
STEROID HORMONES: ACTION
Figure 7-7, steps 1–2a
Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell.
Some steroid hormones also bind to mem-brane receptors that use second messenger systems to create rapid cellular responses.
Steroid hormone receptors are typically in the cytoplasm or nucleus.
Cellmembrane
Interstitialfluid
Cytoplasmicreceptor
Nucleus
Nuclear receptor
Rapid responses
Steroidhormone
Bloodvessel
Proteincarrier
Cell surface receptor
2
1
2a
1
2
2a
STEROID HORMONES: ACTION
Figure 7-7, steps 1–3
Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell.
Some steroid hormones also bind to mem-brane receptors that use second messenger systems to create rapid cellular responses.
Steroid hormone receptors are typically in the cytoplasm or nucleus.
The receptor-hormone complex binds to DNA and activates or represses one or more genes.
Cellmembrane
Interstitialfluid
Cytoplasmicreceptor
Nucleus
Nuclear receptor
DNA
Rapid responses
Steroidhormone
Bloodvessel
Proteincarrier
Cell surface receptor
2
3
1
2a
1
2
2a
3
STEROID HORMONES: ACTION
Figure 7-7, steps 1–4
Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell.
Some steroid hormones also bind to mem-brane receptors that use second messenger systems to create rapid cellular responses.
Steroid hormone receptors are typically in the cytoplasm or nucleus.
The receptor-hormone complex binds to DNA and activates or represses one or more genes.
Activated genes create new mRNA that moves into the cytoplasm.
Cellmembrane
Interstitialfluid
Cytoplasmicreceptor
Nucleus
Nuclear receptor
DNA
Rapid responses
Transcriptionproduces mRNA
Steroidhormone
Bloodvessel
Proteincarrier
Cell surface receptor
2
3
1
4
2a
1
2
2a
3
4
STEROID HORMONES: ACTION
Figure 7-7, steps 1–5
Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell.
Translation produces new proteins for cell processes.
Some steroid hormones also bind to mem-brane receptors that use second messenger systems to create rapid cellular responses.
Steroid hormone receptors are typically in the cytoplasm or nucleus.
The receptor-hormone complex binds to DNA and activates or represses one or more genes.
Activated genes create new mRNA that moves into the cytoplasm.
Cellmembrane
Interstitialfluid
Cytoplasmicreceptor
Endoplasmicreticulum
Nucleus
Nuclear receptor
DNA
Translation
Rapid responses
Transcriptionproduces mRNA
Steroidhormone
Bloodvessel
Proteincarrier
Newproteins
Cell surface receptor
2
3
1
4 5
2a
1
2
2a
3
45
17-22
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THE STRUCTURE OF A G-PROTEIN –LINKED RECEPTOR.
RECEPTORS THAT ACTIVATE G PROTEINS
17-24
17-25
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ANOTHER RECEPTOR – G PROTEIN CYCLE
CAMP AS A SECOND MESSENGER.
c-AMP: a second messenger
OVERVIEW- GENERAL STRUCTURE
Lyase Enzyme that converts ATP to cAMP Interacts with g proteins and receptors 1064-1353 amino acids long 120-150 kilodaltons
GENERAL STRUCTURE CONT’D
10 mammalian isoforms All membrane bound 60% similarity 50%-90% in cytoplasmic regions
PRIMARY STRUCTURE
The main structural features of mammalian adenylyl cyclases
M1/M2: 2 sets 6 transmembrane spans C1a/C1b: large cytoplamic domains (360-390 amino
acids) C2a/C2b: large cytoplasmic domains (255-330 amino
acids) Most highly conserved sequence in all isoforms 50% similar; 25% identical
N terminus and C terminus
ROLE OF CYCLIC AMP
Step 1: activates protein kinasesStep 2: protein kinases phosphorylate substrate proteinsStep 3: activated substrate proteins regulate hormone production
G-protein Mediated cAMP synthesis
bga
GTP
GDP
a
GTP
ATP
cAMP +PPi
bg a
GTP
ATP
cAMP +PPi
GDPPi
When the [hormone] drops…
GDP
GTP
RECEPTORADENYLYL CYCLASE
G PROTEINS THAT INTERACT WITH ADENYLATE CYCLASE
17-35
WHAT DOES IT DO?
17-37
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RECEPTORS THAT DIRECTLY ALTER THE ACTIVITY OF INTRACELLULAR MEDIATOR
17-38
SER
IP3 (inositol triphosphate)
Ca++
G-protein mediated signal transduction is mediated by several 2nd messengers:
DAG(diacyl glycerol) OH
protein kinase C
Ultimateeffects
cAMPprotein kinase A
Adenylate cyclase
Phospholopase C
2ND MESSENGERS: IP3 AND DAG
PLC- active
Phosphatidylinositol- 4,5 biphosphate=(PIP2)
PLC= Phospholipase C
is a membrane phospholipid cleaved into free IP3 and membrane bound DAG by phospholipase C. (Ch.7) (Ch.12)
HYDROLYSIS OF PIP2
phosphatidylinositol 4,5-bisphosphate
One of the most widespread pathways of intracellular signaling is based on
the second messengers derived form PIP2
LE 11-12_1
CYTOSOL
Ca2+Endoplasmicreticulum (ER)
IP3-gatedcalcium channel
IP3 (secondmessenger)
DAG
PIP2G-protein-linkedreceptor Phospholipase C
G protein
Signal molecule(first messenger)
EXTRACELLULARFLUID
GTP
LE 11-12_2
CYTOSOL
Ca2+Endoplasmicreticulum (ER)
IP3-gatedcalcium channel
IP3 (secondmessenger)
DAG
PIP2G-protein-linkedreceptor Phospholipase C
G protein
Signal molecule(first messenger)
EXTRACELLULARFLUID
GTP
Ca2+ (secondmessenger)
LE 11-12_3
CYTOSOL
Ca2+Endoplasmicreticulum (ER)
IP3-gatedcalcium channel
IP3 (secondmessenger)
DAG
PIP2G-protein-linkedreceptor Phospholipase C
G protein
Signal molecule(first messenger)
EXTRACELLULARFLUID
GTP
Ca2+ (secondmessenger)
Variousproteinsactivated
Cellularre-sponses
Ca2+ pool can be affected in 2 ways:
1. Ligand binding to a calcium ion channel
2. Activation of IP3 signaling pathway
G PROTEINS THAT OPEN CALCIUM ION CHANNELS
17-46
17-47
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ligand -gated (IP3)
ligand -gated (Ca2+ )
voltage -gated
P-type Ca2+ pump
P-type Ca2+ pump
HYDROLYSIS OF PIP2
phosphatidylinositol 4,5-bisphosphate
One of the most widespread pathways of intracellular signaling is based on
the second messengers derived form PIP2
Phospholipase C-mediated effects:
•Liver glycogen breakdown (vasopressin)•Pancreatic amylase secretion (acetylcholine)•Platelet aggregation (thrombin)
Protein kinase C effects include:
• neurotransmitter release• cell growth & division• cell differentiation • glycogen hydrolysis• fat synthesis
CALMODULINCalmodulin binds directly with calcium ions to regulate the activity of specific proteins.
Upon binding it undergoes a conformational change allowing binding of other proteins, activating or inactivating them
The protein Calmodulin with calcium binding.
Calcium: bluealpha-Helices: orangebeta-sheets: green.
CALCIUM/CALMODULIN
CA2+ ions
CALMODULIN
#6: THE CALCIUM CALMODULIN COMPLEX REGULATES ENZYME ACTIVITY
Ca+2 triggers
conformation change
CCC
(enzyme)
SIGNAL AMPLIFICATION
17-54
CYTOPLASMIC RESPONSE TO A SIGNAL.
Amplification
cAMP and the Fight-or-Flight Response; activation of PKA
cAMP
adrenaline
inactiveadenylylcyclase
inactiveactive protein kinase A
phosphorylase kinase
p
p glycogenphosphorylase
glycogen glucose-1-phosphate
Liver cell
amplification cascade
cAMP
activeATP
inactive
inactive
active
active
CAFFEINE KEEPS YOU AWAKE BECAUSE IT
1. Prevents the synthesis of cAMP.
2. Prevents the breakdown of cAMP.
3. Inactivates the enzyme protein kinase A.
4. Inhibits the enzyme glycogen phosphorylase
Caffeine inhibits the enzyme phosphodiesterase, which normally breaks down cAMP.
.
Thanks GOOd LUCK
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