Chapter 7- Biosignaling Flashcards
Exam 2
How do cells communicate?
By cell to cell communication that involves proteins working together to create pathways to respond to extracellular signals
How are extracellular signals sensed?
Through cellular receptors on the outside of the cell and are transmitted inside the cells through a SIGNALING CASCADE
What does a signaling cascade do?
Generates a cellular response to the extracellular signals that enter the cell
What is signal transduction?
Biochemical mechanism responsible for transmitting extracellular signals across the membrane
(a mechanism that brings signals from outside the cell through the cell membrane)
What is a ligand? What does it do?
It is known as the first messenger and binds to the receptor protein to trigger a cellular response
What initiates a signal transduction pathway?
The receptor which a ligand binds to
What is the end result of a signal transduction pathway in a cell?
Covalent or noncovalent modification of an intracellular target protein
(activate or inhibit certain cell processes by changing proteins in the cell)
What three things affect the specificity of a response in a target cell?
Type of receptor (that ligand/chemical messenger binds to)
Location of receptor
Specific chemical messenger that binds to the receptor (ligand)
What are the processes that activating a receptor could involve?
Covalent protein modification
Protein conformational (shape) changes
Altering the rate of gene expression
What are the steps of chemical messengers in a cell?
The ligand is secreted from a cell in response to stimulus
The ligand diffuses or is transported through blood or extracellular fluid to target cell
Hydrophobic messages diffuse across plasma membrane to bind to intracellular receptor and elicit a response (or ligand binds to receptor on membrane)
Binding of messenger elicits response or signal is terminated
What are second messengers?
Small, non protein intracellular molecules that amplify receptor generated signals
What are 5 main second messengers in a cell?
cAMP cGMP DAG IP3 Calcium ion
What is DAG (diacylglycerol) made from?
The phospholipids in the membrane
What does adenylate cyclase do during second messaging?
Generates the secondary messenger cAMP from ATP
What does phospholipase C do?
Control the activity of the second messengers
What does DAG do?
Activates protein kinase c (PKC)
What does IP3 do?
Activates Ca2+ channels in the endoplasmic reticulum allowing for increased cytoplasmic levels of Ca2+
What does Ca2+ activate?
Ca2+ binding proteins like calmodulin
What kind of ligands would be used fro cell-surface receptors?
Polar molecules (bind to membrane receptors because they cannot rapidly cross the membrane)
Need to be hydrophobic and small to rapidly diffuse through the membrane
What kind of ligands would be used for intracellular receptors?
Hydrophobic messengers like steroid hormones
able to diffuse through the membrane to bind to intracellular receptors
What kind of receptors are intracellular receptors?
Gene-specific transcription factors
Proteins that bind to a specific site on the DNA and regulates the rate of transcription of a gene - slow process
Why can steroid hormones diffuse across the plasma membrane?
They are lipids (hydrophobic)
How do thyroid hormones enter the cell?
Facilitated diffusion (still not using energy)
How do nuclear receptors function?
They function as transcription factors that regulate gene expression
How are lipophilic hormones transported in the blood?
Bound to serum albumin
Bound to steroid hormone-binding globulin (SHBG)
bound to thyroid hormone-binding globulin (TBG)
What do lipophilic hormones do for transcription of specific genes?
Either activate or inhibit transcription of specific genes
What does ligand binding do to the nuclear receptor?
Causes a conformational (shape) change
This allows it to bind to the DNA
What are hormone response elements?
Short specific sequences of DNA located in promoters of hormone-responsive genes
(activated nuclear receptors bind to HRE)
What do heat shock proteins act as in steroid hormone receptor protein regulation?
They act as regulatory proteins
Glucocorticoid receptor is bound to a HSP and keeps it in its inactive state until cortisol binds to GR
What happens when cortisol attaches to a glucocorticoid receptor?
GR detaches from the heat shock protein and exposes a nuclear localization signal (NLS)
GR then homodimerizes (basically duplicates itself) and goes to the nucleus (through the nuclear pore) where it can now bind to the HRE in the DNA
Map out what is happening in this diagram
- Heat shock proteins are bound to glucocorticoid receptors in the cortisol which causes the GR to be in an inactive state
- Cortisol attaches to GR and releases GR from HSP which reveals a nuclear localization signal
- GR homodimerizes (attaches to another of the same molecule) and creates a GR dimer
- GR dimer translocates (travels) through the nuclear pore (can get in because the pore recognizes the nuclear localization signal) into the nucleus
- GR binds to the hormone response element (HRE) in the DNA next to the gene that needs to be inhibited or expressed
- Transcription of that gene is either activated or inhibited to regulate metabolism
How long does glucocorticoid receptor signaling take?
Days - remember transcription is slow
Where are glucocorticoids synthesized?
They are steroid hormones so they are made in the adrenal glands
What role do activated glucocorticoid receptors play in the body?
They enter the nucleus to inhibit transcription of inflammatory contributing proteins like COX-2
They also induce expression of anti-inflammatory proteins like annexin I
ANTI-INFLAMMATORY
What are the 3 common features of membrane receptors?
Extracellular domain that binds the chemical messenger (binding site on outside of cell)
1 or more membrane-spanning domains that are alpha helices (at least one alpha helix domain)
Intracellular domain that initiates signal transduction (must initiate a response inside the cell to a signal from outside the cell)
How do membrane receptors transmit a signal?
Conformational change on the extracellular domain due to ligand binding that is recognized inside the cell
Activated intracellular domain initiates a signal transduction pathway
Is the signaling pathway bidirectional?
No it only goes in one direction
What are the 3 effects on a cell from signal transduction through membrane receptors?
Rapid and immediate effects of cellular ion concentration
Activation/inhibition of enzymes
Slower changes in the rate of gene expression for a specific set of proteins
What are most G Protein-Coupled Receptors involved in?
Sensory responses of vision, taste and smell
How many alpha helices pass through the membrane for G protein-coupled receptors?
7 passes through the membrane
What does heterotrimeric mean and what proteins are heterotrimeric?
G-proteins are heterotrimeric meaning they have 3 different subunits- alpha, beta, gamma (reminder that this indicates a quaternary structure)
What do G-proteins do?
Bind GTP
What attaches Galpha and Ggamma proteins of the G-protein to the inner plasma membrane leaflet?
Lipid anchors
What do G-proteins do to a signal?
They mediate signal transduction from G Protein-Coupled Receptors to other target proteins
What is bound to G protein when it is inactive?
GDP
Where does GDP exchange for ATP in activated G Protein Complex?
The G alpha protein
What happens to the G-alpha protein subunit when activated?
It dissociates from G-Beta and gamma complexes
What does Gsalpha protein do?
It is a stimulatory protein that activates adenylate cyclase (converts ATP to cAMP)
cAMP is the second messenger here
What does Gialpha do?
It is an inhibitory protein that inhibits adenylate cyclase
What does Gqalpha do?
It is a stimulatory protein that stimulates PLC (phospholipase C)
The second messengers here are IP3, DAG, and Ca2+
Who does epinephrine (E) interact with a cell?
Through G Protein-Coupled Receptors
What is Epinephrine and what does it do?
It is a hormone made in the adrenal glands (lipophilic) and it mediates stress response by the mobilization of energy
Where are the receptors that epinephrine binds to?
Muscle or liver (breakdown glycogen to glucose) Adipose tissue (lipid hydrolysis) Heart cells (increase heart rate)
How many molecules of blood glucose can be released from 1 molecule of epinephrine?
100,000
How does an organism stop glucose synthesis when there is no more need for fight or flight response?
G-alpha acts as a GTPase to break down GTP to GDP which causes the GProtein complex to become inactivated and stop signal transduction
What G-alpha protein binds to GTP during pertusis?
Gi-alpha - An inhibitory protein that inhibits the activation of adenylyl cyclase
Be able to tell what is happening in this figure. Find the GPCR, the G-Protein complex, second messengers, and what channels they open up
- contains the ligand (E) binding to the GPCR
- Shows the Gprotein complex (heterotrimeric)
- Shows the binding of GTP to Gqalpha to activate it
- Shows the Activated Gqa binding to PLC to create the second messengers (DAG and IP3 from PIP2)
- Shows second messenger IP3 (hydrophilic so can travel in the cytoplasm) opening the calcium channel to allow Ca2+ to enter into the cytoplasm from the ER
- Shows Protein Kinase C (PKC) being activated from DAG (stays in membrane because it is hydrophobic) in the membrane and Ca2+ in the cytoplasm
- Kinases transfer a phosphate group to either activate or inactivate responses
How does DAG attach to PKC?
By laterally translocating through the plasma membrane (remember lateral translocation is fast)
What are 3 distinct pathways for primary messengers (ligands) to alter transcription in cells?
- Steroid and Thyroid hormones
- Activation of protein kinases in the cytosol that moves to the nucleus
- Activation of latent transcription factors in the cytosol
What do kinases do?
Transfer a phosphate group from ATP to an OH on a specific amino acid residue on target protein (Ser, Thr, and Tyr)
Where in the membrane is the tyrosine kinase domain?
On the inside leaflet of the cell membrane
What is the ligand for tyrosine kinase receptors?
Growth factor
What happens when 1 growth factor binds to an inactive tyrosine kinase receptor?
The receptor dimerizes (homodimerization) and becomes activated when a second growth factor binds to the new receptor from dimerization
Where are tyrosine kinase receptors phosphorylated?
On the tyrosine domains (on the inside part/ leaflet)
What kind of G protein is RAS?
Ras is a G alpha protein (dissociates)
What kind of bond holds Ras onto the plasma membrane?
Covalent bonds
When is Ras activated?
When it has GTP attached to it
What trio of kinases are part of the Mitogen-activated protein kinase (MAPK) pathway?
Raf, MEK, and ERK
What are the different types of possible target proteins?
Transcription factor
Metabolic enzyme
Cytoskeletal protein
Transport protein
