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Molecular Biology of the Cell Chapter 15 Part 1

Principles of cell communication
STUDY
PLAY
Extracellular chemical signals
For cells in a multicellular organism to function as an organized group they must be able to recognize, and respond to, what?
1. Being able to regulate the signals emitted,
2. Having the released signal recognized by the correct 'receiving' cell,
3. Having the signal 'interpreted' to generate a change in cell behavior
What three things are necessary for cells in a multicellular organism to be able to recognize and respond to extracellular chemical signals?
External signals
Most cells in a multicellular organism can release and receive what?
Single cells that exist in a community
What kind of cells participate in intracellular communication
1. Controlling population density and coordinating motility
2. Influencing antibiotic production, spore formation and sexual conjugation
Bacteria respond to chemical signals secreted by their neighbors for what two functions?
'Quorum sensing'
The signaling process which controls density, coordinates motility, influences antibiotic production, spore formation and sexual conjugation is called what in bacteria?
Single celled and multicellular organisms
The general molecular organization of a signaling pathway are similar for what organisms?
Cell-cell communication
What kind of communication includes receptor proteins, intracellular signaling proteins, and effector proteins?
Receptor proteins
What proteins are often cell surface proteins (several intracellular receptor proteins exist), and are responsible for recognizing the signaling molecule which leads to receptor activation?
Activated receptors
What kind of receptors undergo a conformational change that transmits the signal to an intracellular signaling protein?
On to another protein, which in turn passes it on to another protein in the pathway
The activated intracellular signaling protein passes the signal where?
A signaling cascade
When a signaling protein passes the signal on to another protein, which in turn passes it on establishes a sequence of intracellular signaling events referred to as what?
The effector proteins
The terminal target of internal signaling are what?
Upon their activation
When are effector proteins are altered in some way?
the original signal
Alteration of effector proteins is necessary for implementing the changes dictated by what?
Metabolism, gene expression, cell shape or cell movement
The end result of activation of intracellular signaling may include changes in what?
A: Extracellular signal molecule
B: Receptor protein
C: Intracellular signaling proteins
D: Effector proteins
Identify the structure/signals of the intracellular signaling pathway
A: Altered metabolism
B: Altered gene expression
C: Altered cell shape or movement
Identify the products produced by intracellular signaling pathway
1. Proteins
2. Peptides
3. Amino acids
4. Nucleotides
Give some examples of signaling molecules that use cell surface receptors
1. Steroid hormones
2. Retinoids
3. Vitamin D
4. Nitric oxide (NO)
5. Carbon monoxide (CO)
Give some examples of signaling molecules that use intracellular receptors
Cell-surface receptors and intracellular receptors
What are two different types of receptors?
Cell-surface receptors
Signals such as proteins, peptides, amino acids, or nucleotides are typically recognized by what?
Pass through the plasma membrane to directly bind to intracellular receptors
Small hydrophobic molecules such as steroid hormones, retinoids, and vitamin D as well as dissolved gases like NO and CO can do what?
Within different compartments of the cell
Intracellular receptors may reside where?
Specific at very low concentrations
Signal molecule binding to a receptor is highly what and occurs at what kind of concentrations?
Exocytosis
Signaling molecules are released by the signaling cell by what process?
Plasma membrane
Some signaling molecules can directly diffuse through the cell's what?
Span the plasma membrane and remain tethered to the signaling cell
Some signaling molecules are transmembrane proteins that do what?
Cell-surface receptor
What type of cellular receptor is this?
Intracellular receptor
What type of cellular receptor is this?
"Contact-dependent signaling"
What kind of signaling is it when the signaling molecule remains bound to the extracellular surface of a signaling cell, direct interaction between the signaling cell and the target cell is required?
Events that occur during development and in the immune response
Contact dependent signaling is important for what signaling events?
"Paracrine signaling"
What kind of signaling happens when the signaling molecule acts on neighboring cells the process (the signaling molecule is released by the signaling cell) ?
Different cell types
Paracrine signaling occurs between the same or different cell types?
"Autocrine signaling"
Signaling between the same cell types is called what?
1. Rapid uptake by neighboring cells
2. Degradation by extracellular proteases,
3. Immobilization by extracellular matrix proteins
What mechanisms are used to prevent signal molecule diffusion?
Synaptic and endocrine signaling
Long distance signaling mechanisms include what?
Axonal signaling in neurons
Give an example of synaptic signaling:
Directly to the target cell
Long axonal extension make direct contact with a target cell such that chemical signals released are delivered where?
Signaling molecules (hormones)
In endocrine signaling, endocrine cells secrete their what into the bloodstream
Long distances
How far are hormones carried to act on target cells (short or long distances)
Diffusion and blood flow to carry the signaling molecule to the target cells
Endocrine signaling therefore depends on what? To carry what molecule? To what cells?
A: Contact-dependent
B: Paracrine
C: Synaptic
D: Endocrine
Identify the intracellular signaling pathways?
Slow
Endocrine signaling depends on blood flow for delivery therefore signal transmission is what (fast or slow)?
Synaptic signaling
What kind of signaling is triggered by an electrical signal and is therefore much faster?
Very low concentrations
For endocrine signaling, secreted hormones are diluted in the bloodstream and therefore must be able to function at what concentrations?
High specificity for a particular hormone
Endocrine signaling requires that the target cell express receptors with what?
Very high concentration
For synaptic signaling, neurons release their signaling molecule at what concentration (low or very high) into the extracellular matrix adjacent to the target cells?
Only a low affinity
Synaptic signaling receptors on target cells require what kind of affinity (low or high) for the signal ligand?
A response in different target cells
Endocrine signaling requires that different endocrine cells secrete different hormones to induce what?
Neuronal cells
In synaptic signaling, what cells can use the same signaling molecule to trigger a response in different cells because the synaptic terminii delivers the signal to target cell?
Endocrine signaling
What kind of signaling is this?
Synaptic signaling
What kind of signaling is this?
The method of delivery and the target cells intracellular response to the extracellular signal
Target cell response time to a molecular signal depends on what
Rapid
For signals that induce a change in target cell protein activity, the intracellular response is what (slow or rapid)?
1. Phosphorylation
2. Changes in a proteins subcellular localization
3. Alterations in protein-protein interactions
Changes in protein activity can be induced by what? (three answers)
The desired target cell response
Rapid intracellular responses to an extracellular signal is seen when changes in cell movement, secretion or metabolism is what?
A slow response
Besides rapid responses, extracellular signaling molecules can also induce what kind of response within the target cell
Gene transcription requiring mRNA processing, mRNA export and then protein synthesis
For these signaling molecules, the target cell response involves changes in what? (three answers)
Delivery method of the signaling molecule [rapid (synaptic signaling) or slow (endocrine signaling)]
The two intracellular response pathways [fast (changes in protein activity) or slow (gene transcription)] are not linked to the what?
Fast (<sec to min)
What is the speed of changes in protein changes in A?
Slow (mins to hours)
What is the speed of changes in protein changes in B?
Gap junctions
Transmission of an intracellular response to neighboring cells occurs by the passage of inorganic ions or small water soluble molecules through water-filled channels that directly link adjacent cells. What are these water-filled channels?
Epithelial cells
Where are gap junctions found?
Homogenize the cytoplasm of one cell with its
neighbor
What is the main function of a gap junction?
Intracellular mediators such as calcium or cyclic AMP
Signaling pathways that result in the production of what can transmit this signal to a neighboring cell via passage through gap junctions?
A sympathetic nerve to respond to a signal and pass that intracellular response to an adjacent cell that is not innervated
Cell-cell communication mechanism using gap junctions allows one cell innervated by what? That respond to what? Pass the reponse where? which is not what?
A coordinated manner
Using gap junctions allow cells can respond to extracellular signals in what kind of manner even if not all target cells have bound the signaling molecule?
Gap junction
What is this structure?
Hundreds of different signal molecules
A cell in a multicellular organism is exposed to what?
A target cell response
A cell in a multicellular organism is exposed to hundreds of different signal molecules. It is the combinations of these different signals that induce what?
Different receptors on different target cells
Differential responses are accomplished by the expression of what?
Cell survival, growth, division, differentiation and cell death
Signal molecules work together to regulate what basic functions of the cell?
A: Survive
B: Divide
C: Differentiate
D: Die
Multiple extracellular signals illicit what kind of cellular responses?
Different combinations of extracellulular signal molecules
Cells have different receptors that allows them to respond to what?
Different target cell responses
Different cell types can respond to the same signal to induce what?
Decreased cell contraction,
When the signal molecule acetylcholine is bound to its receptor on a heart muscle, what are the results?
Muscle contraction
When the signal molecule acetylcholine is bound to its receptor on skeletal muscle cells it induces what?
Secretion
When the signal molecule acetylcholine is bound to cell surface receptors on slaivary gland cells, it results in what?
1. Differences in receptors (heart muscle and skeletal muscle cells)
2. Differences in the intracellular signaling pathway activated (heart muscle and salivary gland cells)
The differences in target cell response when different receptors are bound to acetylcholine may be due to what? (2 answers)
B: Decreased rate and force of contraction
C: Muscle contraction
D: Secretion
What are the responses for the heart muscle (B), skeletal muscle cell (C) and salivary gland cell when their receptors are bound by acetylcholine?
The extracellular concentration of the signaling molecule
The same type of target cell can differ in their intracellular response to the same extracellular signal based on what?
The induction of different sets of genes during development
The same type of target cell can differ in their intracellular response to the same extracellular signal based on the extracellular concentration
of the signaling molecule.This differential response is important for what?
Extracellular developmental signals
What are "morphogens"?
The number of signal-receptor complexes activated
The differential response to morphogen concentration is linked to what?
Target cells closest to the source of morphogen have more activated
receptors than target cells furthest from the morphogen source
Which cells have more activated receptors - (the target cells closest to the source of morphogen or the targets furthest away from the source)?
The amount of gene regulatory proteins activated, and in turn, the pattern of gene
expression between cells found along the morphogen gradient will differ
Differences in receptor activation leads to differences in the what?
Transmembrane proteins found in the plasma membrane of target cells
The most familiar signaling receptors are what?
The cytosol
Some signal molecules activate intracellular receptors found where in the target cells?
Nitric Oxide (the gas)
Give an example of a signal molecule that can pass through the target cell's membrane for intracellular receptor binding?
Induces smooth muscle relaxation
What does NO do?
A multistep signaling cascade
This pathway includes acetylcholine release by an
activated neuronal cell as the primary signal molecule triggering an intracellular response in the endothelial cells that line the interior of a blood vessel. What kind of pathway is it?
The adjacent smooth muscle cells
This target cell then becomes the signal cell which releases a signal molecule for the activation of the next target cell in the pathway, what are they?
NO synthase (NOS)
An activated nerve terminal releases acetylcholine, it binds to the receptor on the underlying endothelial cell activating what?
Arginine
Using what as a substrate NOS generates the gas NO?
The cytosol of the smooth muscle cells
NO diffuses out of the endothelial cell and enters what?
Cyclic GMP
In the cytosol, NO binds to its receptor, soluble guanylyl cyclase triggering the enzymatic
conversion of GTP to what?
Muscle relaxation
cGMP then triggers downstream signaling leading to what?
Cytosolic phosphodiesterases
cGMP is rapidly degraded by what?
The nuclear receptor superfamily (transcription factors)
What is a large family of cytosolic proteins that bind to membrane permeable signals such as steriod hormones, thyroid hormone, retinoids and vitamin D?
1. Lose their bound inhibitory proteins
2. Undergo a change in conformation promoting coactivator
3. Protein binding
4. Trigger a change in target gene transcription
With ligand binding these receptor proteins do what? (4 answers)
Translocation into the nucleus for DNA binding
For some cytosolic localized nuclear receptor family members, ligand binding results in their movement where? For what purpose?
DNA transcription
For other receptor proteins ligand binding prevents what from happening to the DNA?
Both intracellular receptors for signal molecule binding and effectors for the
signal
In all cases, nuclear receptor superfamily members act as what? Give two functions
Only half have identified ligands
Of the 48 different nuclear receptor family members identified in the human genome; how many have identified ligands?
'Orphan' nuclear receptors
What are nuclear receptors with unknown ligands?
Inactive receptor
Is this an active receptor or an inactive receptor?
Active receptor
Is this an active receptor or an inactive receptor?
The primary response
For nuclear receptor proteins that activate gene transcription upon ligand binding, the genes that are directly activated constitute what?
A secondary-response
The primary response proteins can then act to activate the transcription of a second set of genes generating a delayed response to the signal molecule which is referred to as a what?
Negative regulatory loop to limit the response of the initial signal
The primary response gene products can turn off the primary-response genes, acting as a what? To limit what?
A combination of transcription factors which are cell type specific
Many cells express the same set of nuclear receptors however the cellular response they induce will vary from cell type to cell type as gene transcription is regulated by what?
Primary response
What type of response is this (primary or secondary)?
Secondary response
What type of response is this (primary or secondary)?
Signal transduction
What is the process by which cell surface receptor proteins convert extracellular
signals into an intracellular one.
1. Ion channel coupled receptors
2. G-protein coupled receptors
3. Enzyme couple receptors
What are the three general classes of cell surface receptors?
Ion channel coupled receptor
What type of receptor is this?
1. It consists of multipass transmembrane proteins
2. It is opened or closed by the binding of neurotransmitters triggering ion permeability across the plasma membrane
3. It is involved in the synaptic signaling between nerve cells and target cells (muscle or nerve cells)
G protein coupled receptor
What type of receptor is this?
1. It consists of multipass transmembrane proteins
2. It is responsible for the indirect activation of a plasma membrane bound enzyme or ion channel via the activation of an intermediary heterotrimeric GTP binding protein complex
3. Activation leads to changes in the concentration of small intracellular mediates or plasma membrane permeability
Enzyme coupled receptors
What type of receptor is this?
1. It is often single pass transmembrane proteins
2. It functions directly as enzymes (left panel in C) or associates with enzymes that they activate
(right panel in C)
3. Signal molecule binding to the extracellular domain of the protein triggers dimerization
resulting in protein kinase activation which is responsible for phosphorylating specific sets of
proteins in the target cell that they activate
G- Protein
What kind of coupled receptor is this?
Enzyme
What kind of coupled receptor is this?
Ion channel
What kind of coupled receptor is this?
G-protein-coupled or enzyme-coupled receptors
Activation of what two coupled receptors is converted into an intracellular signaling cascade that results in a change in cell behavior?
Secondary messenger
The initial extracellular signal is referred to as the 'first messenger' while the small intracellular signaling molecules generated in response to receptor activation are called what?
To spread the signal to distal portions of the cell
What is the function of the secondary messengers?
Cyclic AMP, calcium, and diacylglycerol
What are some examples of second messengers?
Transduce the original signal throughout the cell
Second messengers bind to larger signaling proteins altering their conformation or activity to do what throughout the cell?
1. Relay
2. Scaffold
3. Convert
4. Amplify
5. Integrate
6. Anchor
7. Modulate
Larger intracellular proteins can have a number of different functions within the cell; Give 7 examples:
Phosphorylation or GTP binding
Transmission of an intracellular signal by the proteins in a signaling pathway is typically carried out by one of two mechanisms: what are they?
Switches
For phosphorylation and GTP binding, the signaling proteins behave as simple molecular what?
Between the off and on forms
What two form do the proteins switch when they receive the get the proper signal?
Protein kinases
(Phosphorylation) The addition of a phosphate group is mediated by what?
Protein phosphatases
(Phosphorylation) What are responsible for removing phosphate groups?
Phosphorylation cascades
(Phosphorylation) Signaling pathways that are mediated by phosphorylation are comprised of multiple protein kinases organized into what?
Relay
One protein kinase is activated by phosphorylation, which in turn phosphorylates the next protein kinase in the pathway leading to its activation. This second kinase then phosphorylates the next kinase protein in the pathway. What type of pathway is it?
Often: serine or threonine; Less often: tyrosine
Often protein kinases phosphorylate proteins on what type of residues and less often on what?
Monmeric GTP binding proteins
What kind of binding proteins are GTPases that are regulated by the state of the guanine nucleotide bound?
The transduction of the signal
When bound to GTP, the binding protein is active promoting what?
Its inactivation and termination of the signal
The intrinsic GTPases activity of the protein converts the GTP to GDP leading to what?
GEFs and GAPs
What two additional proteins are responsible for regulating GTP binding proteins?
GEFs
What are guanine nucleotide exchange factors which function to activate GTPases by promoting the release of GDP for GTP leading to its activation?
GAPs
What are GTPase activating proteins that promote the hydrolysis of the bound GTP leading to the shutting off of the signal?
A: Signaling by phosphorylation
B: Signaling by GTP-binding
Identify the molecular switches (A and B)
The activation of two intracellular pathways that converge at protein Y.
Signal molecule binding to two different receptors results in the activation of what?
The propagation of downstream signaling.
It is the phosphorylation at two different sites on protein Y that
results in what?
Complex biological responses (cell survival, growth and proliferation)
Often it is the combination of two extracellular signals that is required to trigger what? Give some examples!
These two pathways converge at a single protein
Signal molecule binding to two different receptors results in the activation of two intracellular pathways. What happens next?
Coincidence detector
Phosphorylation of a converged protein at two different sites is required for the propagation of downstream signaling
This protein is called a "what"?
When both extracellular signals are present simultaneously
When is the only time that coincidence detector is activated?
Large intracellular scaffold proteins
What kind of proteins promote intracellular signaling?
Scaffold proteins
What proteins function to hold a number of signal proteins together into a large complex to facilitate the sequential, efficient and selective propagation of the appropriate intracellular response while avoiding the cross activation of other signaling pathways?
All the time
For some signaling pathways the intracellular signaling proteins (scaffolds) are never associated with the scaffold protein or all the time?
B
Which side (A or B) has activated intracellular signaling proteins?
The receptor protein
For some signal pathways, the assembly of signaling complexes occurs only after an extracellular signal is bound to what?
On the intracellular domain of an activated receptor
Signaling complexes typically form where?
The efficient transfer of the signal
The close association of signaling proteins promotes what?
When the extracellular signal is terminated and the receptor is not longer activated
When does the protein complex disassemble? (two answers)
Phosphoinositides
Activated plasma membrane receptor can result in the
hyperphosphorylation of what?
Hyperphosphorylated phospholipids
What can act as docking sites for intracellular signaling proteins promoting their interaction and stimulating downstream signal activation?
Positive and negative feedback loops
Intracellular signaling pathways can be controlled by what kind of feedback loops?
Positive feedback loop
What kind of feedback loop has output from the activated pathway that stimulates its own production?
Negative feedback loop
What kind of feedback loop has output from an activated pathway acting to inhibit its own production?
A: Positive feeback loop
B: Negative feedback loop
Identify the feedback loops (A and B)
An activated E kinase
An activated protein kinase (S) phosphorylates an inactive E kinase to generate a what?
Its own phosphorylation and activation
The activated E kinase feeds back in the pathway to promote
A protein phosphatase (I)
The phosphorylation of E kinase is counteracted by the activity of a what?
The strength of the feedback loop itself
The biological response of a pathway to a positive feedback loop is dependent on what?
Moderate strength feedback loop
What strength of feedback loop is this? The positive signals act to increase the cells response to the initial signal
Strong positive feedback loop
What strength of feedback loop is this? The final response produced can be significantly different than in the presence of lower levels of activation.
The initial extracellular signal
Strong positive feedback loops can maintain the intracellular signaling response even in the absence of what?
Muscle cell specification
Strong positive feedback loops are responsible for activating the transcription of muscle specific transcription factors necessary for triggering what?
An activated E kinase
An activated protein kinase (S) phosphorylates an inactive E kinase to generate what?
Dephosphorylate, and therefore inactivate, E kinase
Activated E kinase then phosphorylates a protein phosphatase which functions to do what two things?
The upstream phosphatase
The impact of negative feedback loops are controlled in part by the delay time between activation of the E kinase and phosphorylation of what?
Strong but short lived
(negative feedback) How strong and how long is the cellular response with a short delay?
It will oscillate in its signal response
With a long delay between E kinase activation of the resulting negative feedback, what will happen to its signal response?
Desensitization
Prolonged exposure to a stimulus decreases a cell's response to that level of the signal in a process called what?
The absolute level of a stimulus
Desensitization allows a cell to respond to changes in the concentration of an extracellular signal rather than to what?
Endocytosis
Signal molecule bound receptors can be internalized by the process of what?
They can be retained in the endosome or trafficked to the lysosome for degradation
What happens to the endocytosed receptors?
They are reduced
If the endocytosed receptors are retained in the endosome or are degraded in the lysosome, what happens to the number of plasma membrane receptors?
Phosphorylation, methylation or ubiquitination
Signal bound receptors can also be inactivated by post translational modifications such as what?
The propagation of the signal
An inactivation mechanism can block activation of downstream intracellular signaling proteins ultimately blocking what?
An inhibitor protein
What kind of protein can block the signal transduction process by acting between the activated receptor and the downstream intracellular signaling protein?