Lecture 9 and 10 Flashcards
What are the two types of regulation that have to occur for all cellular processes?
Spatial regulation
Temporal regulation
What does spatial regulation do?
Ensures only specific cells respond, or that the process happens in the correct compartment within a cell
What does temporal regulation do?
Ensures the process only happens when and for how long they are required
What call all cells do?
- Grow/proliferate
- Differentiate/specialise
- Move
- Apoptosis
What is a kinase?
An enzyme that catalyses the phosphorylation of a substrate
What is a phosphate groups formula?
PO4^2-
What are the three amino acid groups that protein kinases can phosphorylate in eukaryotes?
Serine
Threonine
Tyrosine
What are the three major effects of phosphorylation of a protein?
- Becomes more hydrophillic
- Conformational change
- Change in activation status
What are gap junctions?
Intercellular connections which allow direct cytoplasmic communication between cells
What characterizes communication in gap junctions?
Small molecules pass freely between cells
What is the name of the protein that make up gap junctions?
Connexin
What is the name given to each of the two subunits that makes up a gap junction?
Connexon (hemichannels)
What do connexons consist of?
6 connexin protein molecules
Where are gap junctions common?
Where rapid communication is important- muscles (heart), nerve tissue
What is the structure of a connexin protein?
4 transmembrane domains, 2 extracellular lops and both intracellular N- and C- terminals
How many different connexins are there in human cells?
24
How are connexins named?
Based on size
Why are there so many different types of connexins?
Composition defines which molecules can pass through gap junction
What are the two groups of gap junction?
Homotypic- both hemi channels the same
Heterotypic- two different hemi channels
What do multiple channels comprise?
A gap junction plaque
What are endocrine glands?
Glands that secrete their products into the blood
What are exocrine glands?
Glands that secrete their products out through ducts
What is an autocrine signal?
When a ligand acts on the same cell that produced the signal
What is a paracrine signal?
When a ligand can act on neighbouring cells
What is a specific type of paracrine signal in which the ligand is on the sending cell and is not released?
Juxtacrine
What name is given to the translation of signals?
Signal transduction
How do hydrophobic ligands enter the cell?
Ligand can cross the plasma membrane and bind to a receptor within the cell
Give an example of a process which involves a hydrophobic ligand
Cortisol signalling
What is cortisol an example of?
A hormone
What metabolic actions is cortisol signalling involved with?
Blood pressure regulation
Suppression of inflammation
How do hydrophillic signals enter the cell?
Ligand cannot cross plasma membrane so binds to transmembrane receptor
Is insulin hydrophilic or hydrophobic?
Hydrophilic
What name is given to the relaying of hydrophilic signals across the cell membrane?
Transmembrane signalling
What is a second messenger?
Small ions or molecules that relay signals between locations, generated intracellularly
What is a signalling cascade?
A series of reactions initiated by a first messanger acting on a receptor
In what ways can signals be intergrated?
- One receptor activates multiple pathways
- Multiple receptors activate on pathway
- Different receptors and different pathways which affect each other
How are signalling proteins activated?
- Binding to other signals
- Conformational change
- Membrane targeting
- Compartmentalisation
- Covalent modifications
What does signal pathway that is the result of insulin binding to the receptor lead to?
Glucose import
Glycogen synthesis
Regulation of gene expression
What type of cell in the pancreas produces insulin?
Beta cells in the Islets of Langerhans
How does insulin reduce blood glucose levels?
Stimulates uptake of glucose into muscle and adipose tissue, stimulates glycogen synthesis
What receptor does insulin bind to?
Tyrosine kinases
What is the structure of the tyrosine kinases receptor
2 alpha subunits
2 beta subunits
What subunits of the receptor does insulin bind to?
Alpha subunits
What happens when insulin binds to the receptor?
A conformational change results in the receptor becoming activated
What happens once the tyrosine kinases receptor becomes activated?
Insulin receptor substrate 1 (IRS) is phosphorylated (tyrosine is phosphorylated)
What is insulin receptor substrate (IRS)?
An adaptor protein
What happens to IRS once it is activated?
It binds to PI3K (a lipid kinase) which is then activated
What does activated PI3K do?
Catalyzes the addition of a phosphate group to the membrane lipid PIP2, converting it to PIP3
What does PIP3 do?
Recruits protein kinases to the inner surface of the plasma membrane, phosphorylating protein kinase Akt
What does activated Akt do?
- Phosphorylates glycogen synthase kinase-3
- GLUT4 moves from vesicles in the cytosol to the plasma membrane
What does phosphorylation of glycogen synthase kinase-3 do?
Reduces its activity, increasing the amount of the more active form of glycogen synthase, enhancing glycogen production
What happens when GLUT4 transporter is inserted into the membrane?
Glucose uptake
Why is insulin signalling a key component of glucose homeostasis?
Stimulates absorption of glucose and its polymerization into glycogen
What is the 2nd messenger in the insulin signaling pathway?
PIP3
What is the signalling molecule in the insulin signalling pathway?
Akt
In what 4 ways are signalling proteins activated?
- Binding to other signalling molecules
- Conformational changes
- Membrane targeting/compartmentalisation
- Covalent modifications
What are three types of plasma membrane receptors?
- Ligand-gated ion channels
- Enzyme-linked receptors
- G protein-coupled receptors (GPCRs)
What are ligand-gated channels?
Channels triggered by the binding of specific substances to the channel protein
What are enzyme linked receptors?
Transmembrane receptors where the binding of a extracellular ligand causes enzymatic activity on the intracellular side
Guanylyl cyclase receptors result in what enzymatic reaction?
Conversion of GTP to cyclic GMP
What does cGMP regulate?
Vasodilation of blood vessels
Ion channel conductance
Apoptosis
Relaxation of muscles etc.
Give an example of a receptor kinase that does not involve a second messenger.
Receptor Serine/Threonine kinases, such as transforming growth factor beta signalling
What is transforming growth factor beta signalling involved in?
Proliferation, differentiation, chemotaxis, immune cells activation
What type of molecule is insulin?
A dimer
What name is given to receptors that bring two monomer ligands together?
Dimerise
How does dimerisation work?
Protein kinase domains on the intercellular domain of the receptors are brought together by interactions on the extracellular domain
What name is given when each subunit of dimerised receptors phosphorylate themselves?
Autophosphorylate
Where is autophosphorylation important?
Cell proliferation, survival, migration, etc.
What are G proteins?
Guanine-nucleotide binding proteins
How do G-protein linked receptors activate G proteins?
Ligand binding causes a conformational change which activates the G protein
Give examples of G protein-linked receptors
Olfactory receptors, norepinephrine, hormone, opioid receptors etc.
What is the structure of G protein-linked receptors?
7 transmembrane alpha helices
N-terminus in extracellular fluid
C-terminus in cytosol
Alternating cytosolic and extracellular loops
What gives G protein-linked receptors their specificity?
Unique messenger binding site
Cytosolic loops
How are G protein-linked receptors regulated?
Many ways
Phosphorylation of amino acids in their cytosolic domain
What does phosphorylation of amino acids in the cytosolic domain of G protein-linked receptors do?
The receptor becomes densensitized
What are the two classes of G proteins?
Large heterotrimeric G proteins
Small monomeric G proteins
What are the 3 subunits of large heterotrimeric G proteins?
G alpha, G beta, G gamma
What do heterotrimeric G proteins do?
Mediate signal transduction through G protein-linked receptors
What subunit of G proteins does GTP/GDP bind to?
Alpha (the largest of the subunits)
In the inactive state, what does the alpha subunit of G-protein bind to?
GDP
What happens when the ligand binds to the G protein-linked receptor?
The receptor binds a G protein, Galpha releases GDP and acquires GTP
What happens when Galpha acquires GTP?
G alpha and Gbetagamma subunits separate/dissociate
What happens to the separated subunits of the activated G protein?
The subunits activate/inhibit target molecules
Give an example of a signal transduction that involves G proteins.
The adenylyl cyclase-cAMP pathway
What is cyclic AMP?
A second messenger molecule important in many biological processes
What is cAMP produces in response to?
Glucagon, adrenaline etc.
In what ways can signals be terminated?
- Second messengers can be catabolised
- Phosphorylation can be reversed
How can signals be terminated when G proteins are involved?
Activity of alpha subunit can be terminated by enzymes such as GTPase
Give an example of second messengers being catabolised.
cAMP/cGMP phosphodiesterase which breaks down cyclic ring
What enzymes can reverse phosphorylation?
Phosphatases
How can signals be amplified?
- By producing more signals
- By preventing signals being turned off
How are more signals produced to amplify a signal?
Increased 2nd messenger synthesis
Give an example of increased 2nd messenger synthesis
Forskolin increases cAMP production
How can signals be prevented from being turned off?
By decreased 2nd messenger degredation, such as when phosphodiesterase mutates
