Lecture 12. Intracellular Signal Transduction: Conserved Mechanisms for Responding to Extracellular Signals Flashcards
What are the seven steps involved in communication by extracellular signals ?
- Synthesis
- Release of signalling molecule by signalling cell
- Transport of signal to target cell
- Detection of signal by specific receptor proteins
- Transduction of signal
- Response
- Termination of signal
What are the general signalling schemes ?
- Endocrine signalling
- Paracrine signalling
- Autocrine signalling
- Signalling by plasma membrane attached proteins
What are the cell surface receptors ?
- G protein coupled receptors
- Ion channel receptors
- Tyrosine kinase linked receptors
- Receptors with intrinsic enzymatic activity
How do G protein coupled receptors work ?
- Ligand binding activates a GTP binding protein.
- This G protein then either activates or inhibits an enzyme that generates a specific second messenger or modulates an ion channel causing a change in membrane potential.
How do ion channel receptors work ?
Ligand binding changes the receptor confirmation such that a specific ion channel is opened
How do tyrosine kinase-linked receptors work ?
Ligand binding stimulates formation of a dimeric receptor which interacts and activates cytosolic protein tyrosine kinase
How do receptors with intrinsic enzymatic activity work ?
Ligand binding changes receptor confirmation and activates catalytic activity
What is an example of a G protein coupled receptor ?
Epinephrine
What is an example of ion channel receptors ?
Acetylcholine
What is an example of tyrosine kinase linked receptors ?
Erythropoietin
What is an example of receptors with intrinsic enzymatic activity ?
Insulin
How do you classify hormones based on their solubility and receptor location ?
- Lipophilic hormones with intracellular receptors
- Lipophilic hormones with cell-surface receptors
- Hydrophilic hormones with cell surface receptors
What are some example of lipophilic hormones with intracellular receptors ?
- Steroid hormones
- Thyroxine
- Vitamin D
What is an example of a lipophilic hormone with cell surface receptors ?
Prostaglandins
What are the two classes of hydrophilic hormones with cell surface receptors and give examples ?
- Peptide hormones for example insulin and glucagon
2. Small charged molecules for example epinephrine and histamine
What are some examples of signal transduction pathways ?
- Epinephrine and B-Adrenergic receptor
- Insulin and insulin receptor
- Epidermal growth factor (EGF) and EGF receptor
What does the epinephrine and B-Adrenergic receptor signal transduction pathway do ?
Energy store mobilisation
What does the insulin and insulin receptor signal transduction pathway do ?
Increase glucose uptake
What does EGF and EGFF receptor signal transduction pathway do ?
Expression of growth promoting genes
What do second messengers do ?
Relay information from receptor-ligand complex
What does binding of ligand to many cell surface receptors lead to ?
Increase or decrease in intracellular signalling molecules ie. second messengers
What are some common second messengers ?
- cAMP, cGMP
- Calcium ion
- Inositol 1,4,5-triphosphate (IP3)
- Diacylglycerol (DAG)
What are second messengers often free to do ?
Diffuse to other compartments of cell for example the nucleus influencing gene expression
What may be amplified in generation of second messengers ?
Signal
What does the use of common second messengers in multiple signalling pathways create ?
Opportunities (cross talk) and potential problems
What is a common means of information transfer ?
Protein phosphorylation
How are proteins phosphorylated ?
Specific enzymes known as protein kinases phosphorylate target proteins
What is the most common donor of phosphate groups ?
ATP
How does a protein kinase phosphorylate ?
Protein kinases transfer phosphoryl groups from ATP to specific serine, threonine and tyrosine residues on specific proteins
What do protein phosphatases do ?
Catalyse the hydrolytic removal of phosphate groups
What are phosphorylation and dephosphorylation reaction not ?
They are not the reverse of one another. They are essentially irreversible under physiological conditions
Where will phosphorylation of a specific substrate only take place ?
In the presence of a specific protein kinase
Where will the dephosphorylation of a specific substrate only take place ?
In the presence of a specific phosphatase
How do protein kinases and phosphatases work together ?
They work independently and in balance to regulate the function of proteins
What type of strategy of phosphorylation ?
A valuable regulatory strategy
What way is the free energy of phosphorylation ?
Very large
What does the large free energy of phosphorylation do ?
Changes the conformational equilibrium between different functional states of the function
What is the most common cellular energy currency ?
ATP
What does the use of ATP as the phosphoryl donor group link ?
The energy status of the cell to regulation of metabolism
What does addition of a phosphate group to the protein do ?
Adds two negative charges to the protein allowing new electrostatic interactions to be formed
What can a phosphate group form ?
Three or more hydrogen bonds
What does the formation of three or more hydrogen bonds allow ?
Specific interactions with other hydrogen bond donors
What is the time frame for phosphorylation and dephosphorylation ?
Can take place within a second and up to hours
What does phosphorylation often result in ?
Highly amplified effects
What amplification mean ?
When enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade
What does cyclic AMP activate ?
Protein kinase A
How does cyclic AMP activate protein kinase A ?
By altering the quaternary structure
What is the structure of protein kinase A ?
Tetramer containing two regulatory R subunits and two catalytic C subunits
What is the other name for the PKA tetramer ?
R2C2
What happens in the absence of cyclic AMP ?
R2C2 is catalytically inactive
What are G protein coupled receptors responsible for ?
Relaying information from many diverse signals for example photons, hormones, neurotransmitters
What is the structure of G protein coupled receptors ?
Contain seven helices that span the membrane bilayer: seven transmembrane helix (7TM) receptors
What in the G protein coupled receptor changes confirmation in response to ligand binding ?
They cytoplasmic loops and C-termini
What does the conformational changes in the cytoplasmic loops and c-termini result in ?
The activation of G-proteins
What are some of the biological functions mediated by G-protein coupled receptors or 7TM receptors ?
- Smell
- Taste
- Neurotransmission
- Hormone action
- Hormone secretion
- Control of blood pressure
- Embryogenesis
- Development
- Vision
- Viral infection
What does rhodopsin take part in ?
Visual signal transduction
Where is the ligand binding site of of G-protein coupled receptors rhodopsin ?
Near the extracellular surface
What is the importance of G-protein coupled receptors ?
- Involvement in many diseases
- Target of almost half of all modern pharmaceutical drugs
3.
In heterotrimeric G-proteins what does the alpha subunit bind ?
Nucleotide
What is the structure of the beta subunit in the heterotrimeric G-protein ?
Seven bladed propeller structure
What is the structure of the gamma subunit in the heterotrimeric G-protein ?
Pair of alpha helices that wrap around the beta subunit
Where are the alpha and gamma subunit of the heterotrimeric G-protein usually anchored to and by what ?
The membrane by covalently attached fatty acids
What happens to the alpha subunit once GTP binds to it ?
It changes conformation and dissociates from the beta- gamma dimer
How do activated G proteins transmit signals ?
By binding to other proteins, often enzymes
What do GDP and GTP act as ?
on/off molecular switches
What are the important classes of molecules involved in signal transduction pathways ?
- Signalling molecules
- Receptors
- G proteins
- Effector enzymes
- Second messengers
- Protein kinases
- Phosphatases
What is an example of an effector enzyme ?
Adenylate cyclase
