Chapter 15 Flashcards
1
Q
What are the three types of extracellular signalling
A
- Autocrine: a cell produces and responds to its signal
- Paracrine: signals travel short distances
- Endocrine: signals travel into the bloodstream to far target cells
2
Q
What is a second messenger
A
- Molecules in the cell to transmit info from the receptor to target protein
3
Q
What enzymes regulate protein phosphorylation in signalling pathways
A
- Kinases: Adds phosphate group to activate function
- Phosphatases: Removes phosphate groups to deactivate function
4
Q
What is signal transduction
A
- The process of converting outer signals to responses in the cell, involving proteins
5
Q
4 ways protein phosphorylation can alter its behaviour
A
- Activating/inactivating an enzyme
- Increasing/decreasing protein-protein interactions
- Changing protein location
- Trigger protein degradation
6
Q
What are G-protein coupled receptors (GPCRs)?
A
- They are a 7-α-helical-domain transmembrane protein that work with G-proteins (2º messenger) to transduct signals
7
Q
Explain how GPCRs transduct signals
A
- The ligand binds which changes its conformation
- GDP -> GTP at the Gα subunit to allow effector association
- Gα binds to adenylyl cyclase which produces cyclic AMP
8
Q
What is the role of heterotrimeric G proteins in GPCR signalling
A
- 3 subunits (α, β, γ)
- The Gα subunit can be activated by GTP phosphorylation (GPCR kinase) and deactivated by hydrolysis (GTPase)
- Activation will allow is to turn on downstream effectors
9
Q
GPCR toxins
A
- Cholera toxin: adenylate cyclase activation = GTPase activity inhibition = intestinal water loss
- Pertussis toxin: inactivates Gα which causes immune defence inhibition
10
Q
3 types of G proteins
A
- Gs: activates adenylyl cyclase which will increase cAMP production
- Gi: inhibits adenylyl cyclase which will reduce cAMP levels
- Gq: activates phospholipase C, which = DAG and IP3 as 2º messengers from the hydrolysis of PIP2
11
Q
The role of adenylyl cyclase
A
- Converts ATP into cAMP, (2º messenger) which will activate downstream proteins (protein kinase A)
12
Q
What are desensitizing/internalization of GPCR signals
A
- Desensitization: less responsive activity by phosphorylation and arrestin binding
- Internalization: they’re endocytosed, reducing their presence on the cell surface
13
Q
3 second messengers
A
- cAMP: activates protein kinase A for phosphylation, degraded to AMP by phosphodiesterase (PDE)
- Diacylgylcerol (DAG): activates protein kinase C to phosphorylate serine and threonine residues on proteins
- Inositol triphosphate (IP3): formed at the membrane, bind to receptor at smooth ER which is a Ca2+ channel. Binding to the channel triggers Ca2+ release from the ER which activate Ca2+-binding proteins (calmodulin)
14
Q
What does epinephrine do in different subunits (specificity)
A
- In cardiac muscles it activates the Gαs subunit -> cAMP production -> increased rate and force of contraction
- In intestinal smooth muscles it activates the Gαi subunit -> no cAMP production -> muscle relax
15
Q
How are blood glucose levels regulated
A
- Hormone binds to its receptor, Gαs subunit activating adenylyl cyclase to convert ATP to cAMP
cAMP is synthesized leading to the reaction cascade (diffusion into the cytoplasm to bind to PKA) - PKA can translocate to the nucleus to phosphorylate CREB which binds to CRE elements on DNA
- Gluconeogenesis is a pathway thats encoded by genes of nearby CREs
16
Q
The role of GPCRs in sensory perception
A
- rhodopsin: GPCR for black-and-white vision, color receptors in the cones are GPCRs
- the distal tips of neurons have odorant receptors that are found in the nose
17
Q
What are receptor protein-tyrosine kinases
A
- They’re receptors that dimerize and auto phosphorylate (trans) tyrosine residues on their cytoplasmic ends to initiate signalling cascades
- Activated by extracellular growth and non-receptor ones are regulated indirectly by extracellular signals
18
Q
Explain protein kinase activation
A
- After the kinases are phosphorylated by the tyrosine resides at their activation loop, it is stabilized to position away from its active site which will activate its kinase domain
- Subunits phosphorylate each other on tyrosine residues that are on adjacent region which will act ad binding sites for cellular signalling proteins
19
Q
What is SH2
A
- Src Homology 2 are domains found on effector proteins that bind to phosphorylated tyrosine residues on RTKs to recruits downstream proteins
- another is a phosphotyrosine-binding domain
20
Q
How are RTK signals terminated
A
- By receptor internalization (clathrin-mediated endocytosis), degradation or dephosphorylation (phosphatases)
21
Q
WHat do SH2 and PTB domain proteins have
A
- Adaptor proteins (bind other proteins)
- Docking proteins (other tyrosine phosphorylation site supply)
- Signalling enzymes
- Transcription factors
22
Q
What is the role of Ras in RTK signalling
A
- A small GTPase that activates downstream signalling proteins in its GTP-bound form
23
Q
How is Ras activity regulated
A
- Guanine Exchange Factors (GEFs): they activate Ras by exchanging GDP for GTP
- GTPase-Activating Proteins (GAPs): they inactivate Ras by promoting GTP hydrolysis
- Guanine Dissociation Inhibitors (GDIs): they inhibit the release of GDP
24
Q
What is the MAP kinase cascade
A
- a series of protein kinases that amplify/propagate signals from RTKs or GPCRs
- Ras activates Raf which is the first kinase and then the signal amplification is initiated
- Terminated by dephosphorylation of kinases (phosphatase) and feedback inhibition mechanisms
25
3 main kinases in the MAP kinase cascade
- **MAP kinase^3 (MAPKKK or Raf)**: this **initiates** the cascade
- **MAP kinase ^2 (MAPKK or MEK)**: this phosphorylate MAPK
- **MAP kinase (MAPK or ERK)**: phosphorylate downstream targets (transcription factors)
26
Scaffolding proteins in the MAP kinase cascade
- They organize the kinases into specific complexes, increasing their efficiency and specificity of the cascade
27
Signalling by the insulin receptor
- Blood glucose **rise** => ß-cells of the pancreas **secrete insulin**
- Blood glucose **falls** => α-cells secrete **glucagon**
- **insulin** is an extracellular messenger that cause cells to **increase** glucose uptake and **decrease** gluconeogenesis when glucose levels are **high**
28
The insulin receptor
- It has an α and ß chain linked together by **disulfide bonds**
- It is activated through **juxtaposition** of the kinases domains => **trans-auto phosphorylation** which makes it a RTK
29
What are insulin-receptor substrates **(IRSs)**
- They’re adaptor proteins, providing binding sites for **SH2 domain-containing signalling proteins** (PI 3-kinase, Grb2, Shp2)
30
What is PI 3-kinase
- Promotes **cell growth, survival and metabolsim**
- One subunit with **two SH2 domains** and the other with a **catalytic domain**
- PI3K phosphorylate PIP2 to **PIP3** (2º messenger) that remain in the **cytosolic leaflet** to provide binding sites for PH domain-containing signalling proteins like **PKB and PDK1** (serine-threonine kinases)
31
How does PKB regulate glucose uptake
- By controlling GLUT4 receptors, tethered to the **cis-Golgi network** by TUG protein
32
PI3-PKB pathway effect on insulin
- When the pathway is activated, it **decreases GSK-3 kinase** activity, leading to an **increased** glycogen synthase activity
- Type 1 diabetes: inability to **produce insulin**
- Type 2 diabetes: insulin overstimulates target cells => insulin resistance & increased glucose levels
33
Signal molecules in plants that are different from animals
- Plants use Ca2+ and phosphoinositide messengers but lack cyclic nucleotides and RTKs
34
What is the role of Ca2+ as a 2º messenger
- Increased levels trigger **smooth muscle cell contraction** by activating Ca2+-sensitive proteins (**calmodulin**)
- [Ca2+] is kept low by closing ion channels in the **plasma and ER membranes** by pumping Ca2+ out of the cytosol by **IP3 and Ca2+ channels**
35
What are the two types if Ca2+ ion channels in the ER membrane
- **IP3 receptors and ryanodine receptors**
- In **Ca2+-induced Ca2+ release (CICR)**, its influx in the membrane induces the opening of ryanodine receptors in the ER => Ca2+ **release into the cytosol**
36
How does the sperm contact with an egg trigger a **Ca2+ response**
- It induces a dramatic Ca2+ cytoplasmic rise, activation cycling-dependent kinases that drive the zygote’s **first mitotic division**
37
What is store-operated Ca2+ entry (SOCE)
- Depletion of Ca2+ levels in the ER triggers Ca2+ channels in the membrane to **open**
38
Example of proteins activated by Ca2+
- Troponin C
- Calmodulin
- IP3 receptor
39
What is the difference between **convergence** and **divergence**
- Convergence: when signals from **unrelated receptors** activate a common effector (GPCRs, RTKs and can lead to a **docking site for Grb2** (Ras))
- Divergence: a **single signal** is sent along many pathways to activate different effectors
- Crosstalk: when signals are passed **back and forth** between difference pathways (cAMP and Ca2+ influencing the other’s pathway)
40
What is the role of nitric oxide (NO) in **smooth muscle relaxation**
- Stimulates guanylyl cyclase => cGMP => decreases **cytosolic Ca2+** => smooth muscles relax
41
What’s does Viagra target in the NO pathway
- **Inhibits cGMP phosphodiesterase (PDE5)** to prevent cGMP degradation, prolonged relaxation
- Male arousal: blood vessels of the penile smooth muscles are **relaxed** by NO leading to **blood engorgement**
42
What enzymes are central to **apoptosis**
- Caspases: cleave cellular proteins , the main proteolytic enzymes in apoptosis
43
Explain the **extrinsic** pathway of apoptosis
- Initiated by **external signals** (the binding of TNF to its receptor, recruiting **procaspases** => **caspases**)
- Caspase activate **executioner caspases => apoptosis**
44
Explain the **intrinsic** pathway of apoptosis
- Initiated by **intracellular** signals
- Cytochrome c release from the mitochondria to the **cytosol** where it forms an **apoptosome** with procaspase-9
45
What is the role of pro- and anti-apoptotic proteins
- Pro-: promote **cytochrome c release**
- Anti-: **inhibit** this release to control cell fate
- Cells are cleared by **phagocytosis**
