Chapter 15 Flashcards
1
Q
For cells in a multicellular organism to function as an organized group they must be able to recognize, and respond to, what?
A
Extracellular chemical signals
2
Q
What three things are necessary for cells in a multicellular organism to be able to recognize and respond to extracellular chemical signals?
A
- 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
3
Q
Most cells in a multicellular organism can release and receive what?
A
External signals
4
Q
What kind of cells participate in intracellular communication
A
Single cells that exist in a community
5
Q
Bacteria respond to chemical signals secreted by their neighbors for what two functions?
A
- Controlling population density and coordinating motility 2. Influencing antibiotic production, spore formation and sexual conjugation
6
Q
The signaling process which controls density, coordinates motility, influences antibiotic production, spore formation and sexual conjugation is called what in bacteria?
A
‘Quorum sensing’
7
Q
The general molecular organization of a signaling pathway are similar for what organisms?
A
Single celled and multicellular organisms
8
Q
What kind of communication includes receptor proteins, intracellular signaling proteins, and effector proteins?
A
Cell-cell communication
9
Q
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?
A
Receptor proteins
10
Q
What kind of receptors undergo a conformational change that transmits the signal to an intracellular signaling protein?
A
Activated receptors
11
Q
The activated intracellular signaling protein passes the signal where?
A
On to another protein, which in turn passes it on to another protein in the pathway
12
Q
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?
A
A signaling cascade
13
Q
The terminal target of internal signaling are what?
A
The effector proteins
14
Q
When are effector proteins are altered in some way?
A
Upon their activation
15
Q
Alteration of effector proteins is necessary for implementing the changes dictated by what?
A
the original signal
16
Q
The end result of activation of intracellular signaling may include changes in what?
A
Metabolism, gene expression, cell shape or cell movement
17
Q
Identify the structure/signals of the intracellular signaling pathway
A
A: Extracellular signal molecule B: Receptor protein C: Intracellular signaling proteins D: Effector proteins
18
Q
Identify the products produced by intracellular signaling pathway
A
A: Altered metabolism B: Altered gene expression C: Altered cell shape or movement
19
Q
Give some examples of signaling molecules that use cell surface receptors
A
- Proteins 2. Peptides 3. Amino acids 4. Nucleotides
20
Q
Give some examples of signaling molecules that use intracellular receptors
A
- Steroid hormones 2. Retinoids 3. Vitamin D 4. Nitric oxide (NO) 5. Carbon monoxide (CO)
21
Q
What are two different types of receptors?
A
Cell-surface receptors and intracellular receptors
22
Q
Signals such as proteins, peptides, amino acids, or nucleotides are typically recognized by what?
A
Cell-surface receptors
23
Q
Small hydrophobic molecules such as steroid hormones, retinoids, and vitamin D as well as dissolved gases like NO and CO can do what?
A
Pass through the plasma membrane to directly bind to intracellular receptors
24
Q
Intracellular receptors may reside where?
A
Within different compartments of the cell
25
Signal molecule binding to a receptor is highly what and occurs at what kind of concentrations?
Specific at very low concentrations
26
Signaling molecules are released by the signaling cell by what process?
Exocytosis
27
Some signaling molecules can directly diffuse through the cell's what?
Plasma membrane
28
Some signaling molecules are transmembrane proteins that do what?
Span the plasma membrane and remain tethered to the signaling cell
29
What type of cellular receptor is this?
Cell-surface receptor
30
What type of cellular receptor is this?
Intracellular receptor
31
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?
Contact-dependent signaling
32
Contact dependent signaling is important for what signaling events?
Events that occur during development and in the immune response
33
What kind of signaling happens when the signaling molecule acts on neighboring cells the process (the signaling molecule is released by the signaling cell) ?
Paracrine signaling
34
Paracrine signaling occurs between the same or different cell types?
Different cell types
35
Signaling between the same cell types is called what?
Autocrine signaling
36
What mechanisms are used to prevent signal molecule diffusion?
1. Rapid uptake by neighboring cells 2. Degradation by extracellular proteases, 3. Immobilization by extracellular matrix proteins
37
Long distance signaling mechanisms include what?
Synaptic and endocrine signaling
38
Give an example of synaptic signaling:
Axonal signaling in neurons
39
Long axonal extension make direct contact with a target cell such that chemical signals released are delivered where?
Directly to the target cell
40
In endocrine signaling, endocrine cells secrete their what into the bloodstream
Signaling molecules (hormones)
41
How far are hormones carried to act on target cells (short or long distances)
Long distances
42
Endocrine signaling therefore depends on what? To carry what molecule? To what cells?
Diffusion and blood flow to carry the signaling molecule to the target cells
43
Identify the intracellular signaling pathways?
A: Contact-dependent B: Paracrine C: Synaptic D: Endocrine
44
Endocrine signaling depends on blood flow for delivery therefore signal transmission is what (fast or slow)?
Slow
45
What kind of signaling is triggered by an electrical signal and is therefore much faster?
Synaptic signaling
46
For endocrine signaling, secreted hormones are diluted in the bloodstream and therefore must be able to function at what concentrations?
Very low concentrations
47
Endocrine signaling requires that the target cell express receptors with what?
High specificity for a particular hormone
48
For synaptic signaling, neurons release their signaling molecule at what concentration (low or very high) into the extracellular matrix adjacent to the target cells?
Very high concentration
49
Synaptic signaling receptors on target cells require what kind of affinity (low or high) for the signal ligand?
Only a low affinity
50
Endocrine signaling requires that different endocrine cells secrete different hormones to induce what?
A response in different target cells
51
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?
Neuronal cells
52
What kind of signaling is this?
Endocrine signaling
53
What kind of signaling is this?
Synaptic signaling
54
Target cell response time to a molecular signal depends on what
The method of delivery and the target cells intracellular response to the extracellular signal
55
For signals that induce a change in target cell protein activity, the intracellular response is what (slow or rapid)?
Rapid
56
Changes in protein activity can be induced by what? (three answers)
1. Phosphorylation 2. Changes in a proteins subcellular localization 3. Alterations in protein-protein interactions
57
Rapid intracellular responses to an extracellular signal is seen when changes in cell movement, secretion or metabolism is what?
The desired target cell response
58
Besides rapid responses, extracellular signaling molecules can also induce what kind of response within the target cell
A slow response
59
For these signaling molecules, the target cell response involves changes in what? (three answers)
Gene transcription requiring mRNA processing, mRNA export and then protein synthesis
60
The two intracellular response pathways [fast (changes in protein activity) or slow (gene transcription)] are not linked to the what?
Delivery method of the signaling molecule [rapid (synaptic signaling) or slow (endocrine signaling)]
61
What is the speed of changes in protein changes in A?
Fast (
62
What is the speed of changes in protein changes in B?
Slow (mins to hours)
63
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?
Gap junctions
64
Where are gap junctions found?
Epithelial cells
65
What is the main function of a gap junction?
Homogenize the cytoplasm of one cell with its neighbor
66
Signaling pathways that result in the production of what can transmit this signal to a neighboring cell via passage through gap junctions?
Intracellular mediators such as calcium or cyclic AMP
67
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 sympathetic nerve to respond to a signal and pass that intracellular response to an adjacent cell that is not innervated
68
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?
A coordinated manner
69
What is this structure?
Gap junction
70
A cell in a multicellular organism is exposed to what?
Hundreds of different signal molecules
71
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?
A target cell response
72
Differential responses are accomplished by the expression of what?
Different receptors on different target cells
73
Signal molecules work together to regulate what basic functions of the cell?
Cell survival, growth, division, differentiation and cell death
74
Multiple extracellular signals illicit what kind of cellular responses?
A: Survive B: Divide C: Differentiate D: Die
75
Cells have different receptors that allows them to respond to what?
Different combinations of extracellulular signal molecules
76
Different cell types can respond to the same signal to induce what?
Different target cell responses
77
When the signal molecule acetylcholine is bound to its receptor on a heart muscle, what are the results?
Decreased cell contraction,
78
When the signal molecule acetylcholine is bound to its receptor on skeletal muscle cells it induces what?
Muscle contraction
79
When the signal molecule acetylcholine is bound to cell surface receptors on slaivary gland cells, it results in what?
Secretion
80
The differences in target cell response when different receptors are bound to acetylcholine may be due to what? (2 answers)
1. Differences in receptors (heart muscle and skeletal muscle cells) 2. Differences in the intracellular signaling pathway activated (heart muscle and salivary gland cells)
81
What are the responses for the heart muscle (B), skeletal muscle cell (C) and salivary gland cell when their receptors are bound by acetylcholine?
B: Decreased rate and force of contraction C: Muscle contraction D: Secretion
82
The same type of target cell can differ in their intracellular response to the same extracellular signal based on what?
The extracellular concentration of the signaling molecule
83
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?
The induction of different sets of genes during development
84
What are "morphogens"?
Extracellular developmental signals
85
The differential response to morphogen concentration is linked to what?
The number of signal-receptor complexes activated
86
Which cells have more activated receptors - (the target cells closest to the source of morphogen or the targets furthest away from the source)?
Target cells closest to the source of morphogen have more activated receptors than target cells furthest from the morphogen source
87
Differences in receptor activation leads to differences in the what?
The amount of gene regulatory proteins activated, and in turn, the pattern of gene expression between cells found along the morphogen gradient will differ
88
The most familiar signaling receptors are what?
Transmembrane proteins found in the plasma membrane of target cells
89
Some signal molecules activate intracellular receptors found where in the target cells?
The cytosol
90
Give an example of a signal molecule that can pass through the target cell's membrane for intracellular receptor binding?
Nitric Oxide (the gas)
91
What does NO do?
Induces smooth muscle relaxation
92
This pathway includes acetylcholine release by an
A multistep signaling cascade
93
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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?
94
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?
The adjacent smooth muscle cells
95
An activated nerve terminal releases acetylcholine, it binds to the receptor on the underlying endothelial cell activating what?
NO synthase (NOS)
96
Using what as a substrate NOS generates the gas NO?
Arginine
97
NO diffuses out of the endothelial cell and enters what?
The cytosol of the smooth muscle cells
98
In the cytosol, NO binds to its receptor, soluble guanylyl cyclase triggering the enzymatic
Cyclic GMP
99
http://o.quizlet.com/uAJm-7kK3PTW88OhD-8TuQ.png
conversion of GTP to what?
100
cGMP then triggers downstream signaling leading to what?
Muscle relaxation
101
cGMP is rapidly degraded by what?
Cytosolic phosphodiesterases
102
What is a large family of cytosolic proteins that bind to membrane permeable signals such as steriod hormones, thyroid hormone, retinoids and vitamin D?
The nuclear receptor superfamily (transcription factors)
103
With ligand binding these receptor proteins do what? (4 answers)
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
104
For some cytosolic localized nuclear receptor family members, ligand binding results in their movement where? For what purpose?
Translocation into the nucleus for DNA binding
105
For other receptor proteins ligand binding prevents what from happening to the DNA?
DNA transcription
106
In all cases, nuclear receptor superfamily members act as what? Give two functions
Both intracellular receptors for signal molecule binding and effectors for the signal
107
Of the 48 different nuclear receptor family members identified in the human genome; how many have identified ligands?
Only half have identified ligands
108
What are nuclear receptors with unknown ligands?
'Orphan' nuclear receptors
109
Is this an active receptor or an inactive receptor?
Inactive receptor
110
Is this an active receptor or an inactive receptor?
Active receptor
111
For nuclear receptor proteins that activate gene transcription upon ligand binding, the genes that are directly activated constitute what?
The primary response
112
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?
A secondary-response
113
The primary response gene products can turn off the primary-response genes, acting as a what? To limit what?
Negative regulatory loop to limit the response of the initial signal
114
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?
A combination of transcription factors which are cell type specific
115
What type of response is this (primary or secondary)?
Primary response
116
What type of response is this (primary or secondary)?
Secondary response
117
What is the process by which cell surface receptor proteins convert extracellular signals into an intracellular one.
Signal transduction
118
What are the three general classes of cell surface receptors?
1. Ion channel coupled receptors 2. G-protein coupled receptors 3. Enzyme couple receptors
119
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)
Ion channel coupled receptor
120
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
G protein coupled receptor
121
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
Enzyme coupled receptors
122
What kind of coupled receptor is this?
G- Protein
123
What kind of coupled receptor is this?
Enzyme
124
What kind of coupled receptor is this?
Ion channel
125
Activation of what two coupled receptors is converted into an intracellular signaling cascade that results in a change in cell behavior?
G-protein-coupled or enzyme-coupled receptors
126
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?
Secondary messenger
127
What is the function of the secondary messengers?
To spread the signal to distal portions of the cell
128
What are some examples of second messengers?
Cyclic AMP, calcium, and diacylglycerol
129
Second messengers bind to larger signaling proteins altering their conformation or activity to do what throughout the cell?
Transduce the original signal throughout the cell
130
Larger intracellular proteins can have a number of different functions within the cell; Give 7 examples:
1. Relay 2. Scaffold 3. Convert 4. Amplify 5. Integrate 6. Anchor 7. Modulate
131
Transmission of an intracellular signal by the proteins in a signaling pathway is typically carried out by one of two mechanisms: what are they?
Phosphorylation or GTP binding
132
For phosphorylation and GTP binding, the signaling proteins behave as simple molecular what?
Switches
133
What two form do the proteins switch when they receive the get the proper signal?
Between the off and on forms
134
(Phosphorylation) The addition of a phosphate group is mediated by what?
Protein kinases
135
(Phosphorylation) What are responsible for removing phosphate groups?
Protein phosphatases
136
(Phosphorylation) Signaling pathways that are mediated by phosphorylation are comprised of multiple protein kinases organized into what?
Phosphorylation cascades
137
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?
Relay
138
Often protein kinases phosphorylate proteins on what type of residues and less often on what?
Often: serine or threonine; Less often: tyrosine
139
What kind of binding proteins are GTPases that are regulated by the state of the guanine nucleotide bound?
Monmeric GTP binding proteins
140
When bound to GTP, the binding protein is active promoting what?
The transduction of the signal
141
The intrinsic GTPases activity of the protein converts the GTP to GDP leading to what?
Its inactivation and termination of the signal
142
What two additional proteins are responsible for regulating GTP binding proteins?
GEFs and GAPs
143
What are guanine nucleotide exchange factors which function to activate GTPases by promoting the release of GDP for GTP leading to its activation?
GEFs
144
What are GTPase activating proteins that promote the hydrolysis of the bound GTP leading to the shutting off of the signal?
GAPs
145
Identify the molecular switches (A and B)
A: Signaling by phosphorylation B: Signaling by GTP-binding
146
Signal molecule binding to two different receptors results in the activation of what?
The activation of two intracellular pathways that converge at protein Y.
147
It is the phosphorylation at two different sites on protein Y that
The propagation of downstream signaling.
148
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results in what?
149
Often it is the combination of two extracellular signals that is required to trigger what? Give some examples!
Complex biological responses (cell survival, growth and proliferation)
150
Signal molecule binding to two different receptors results in the activation of two intracellular pathways. What happens next?
These two pathways converge at a single protein
151
Phosphorylation of a converged protein at two different sites is required for the propagation of downstream signaling. This protein is called a "what?"
Coincidence detector
152
When is the only time that coincidence detector is activated?
When both extracellular signals are present simultaneously
153
What kind of proteins promote intracellular signaling?
Large intracellular scaffold proteins
154
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?
Scaffold proteins
155
For some signaling pathways the intracellular signaling proteins (scaffolds) are never associated with the scaffold protein or all the time?
All the time
156
Which side (A or B) has activated intracellular signaling proteins?
B
157
For some signal pathways, the assembly of signaling complexes occurs only after an extracellular signal is bound to what?
The receptor protein
158
Signaling complexes typically form where?
On the intracellular domain of an activated receptor
159
The close association of signaling proteins promotes what?
The efficient transfer of the signal
160
When does the protein complex disassemble? (two answers)
When the extracellular signal is terminated and the receptor is not longer activated
161
Activated plasma membrane receptor can result in the
Phosphoinositides
162
http://o.quizlet.com/OwdLjsPHld8HfPZV1dul1Q.png
hyperphosphorylation of what?
163
What can act as docking sites for intracellular signaling proteins promoting their interaction and stimulating downstream signal activation?
Hyperphosphorylated phospholipids
164
Intracellular signaling pathways can be controlled by what kind of feedback loops?
Positive and negative feedback loops
165
What kind of feedback loop has output from the activated pathway that stimulates its own production?
Positive feedback loop
166
What kind of feedback loop has output from an activated pathway acting to inhibit its own production?
Negative feedback loop
167
Identify the feedback loops (A and B)
A: Positive feeback loop B: Negative feedback loop
168
An activated protein kinase (S) phosphorylates an inactive E kinase to generate a what?
An activated E kinase
169
The activated E kinase feeds back in the pathway to promote
Its own phosphorylation and activation
170
The phosphorylation of E kinase is counteracted by the activity of a what?
A protein phosphatase (I)
171
The biological response of a pathway to a positive feedback loop is dependent on what?
The strength of the feedback loop itself
172
What strength of feedback loop is this? The positive signals act to increase the cells response to the initial signal
Moderate strength feedback loop
173
What strength of feedback loop is this? The final response produced can be significantly different than in the presence of lower levels of activation.
Strong positive feedback loop
174
Strong positive feedback loops can maintain the intracellular signaling response even in the absence of what?
The initial extracellular signal
175
Strong positive feedback loops are responsible for activating the transcription of muscle specific transcription factors necessary for triggering what?
Muscle cell specification
176
An activated protein kinase (S) phosphorylates an inactive E kinase to generate what?
An activated E kinase
177
Activated E kinase then phosphorylates a protein phosphatase which functions to do what two things?
Dephosphorylate, and therefore inactivate, E kinase
178
The impact of negative feedback loops are controlled in part by the delay time between activation of the E kinase and phosphorylation of what?
The upstream phosphatase
179
(negative feedback) How strong and how long is the cellular response with a short delay?
Strong but short lived
180
With a long delay between E kinase activation of the resulting negative feedback, what will happen to its signal response?
It will oscillate in its signal response
181
Prolonged exposure to a stimulus decreases a cell's response to that level of the signal in a process called what?
Desensitization
182
Desensitization allows a cell to respond to changes in the concentration of an extracellular signal rather than to what?
The absolute level of a stimulus
183
Signal molecule bound receptors can be internalized by the process of what?
Endocytosis
184
What happens to the endocytosed receptors?
They can be retained in the endosome or trafficked to the lysosome for degradation
185
If the endocytosed receptors are retained in the endosome or are degraded in the lysosome, what happens to the number of plasma membrane receptors?
They are reduced
186
Signal bound receptors can also be inactivated by post translational modifications such as what?
Phosphorylation, methylation or ubiquitination
187
An inactivation mechanism can block activation of downstream intracellular signaling proteins ultimately blocking what?
The propagation of the signal
188
What kind of protein can block the signal transduction process by acting between the activated receptor and the downstream intracellular signaling protein?
An inhibitor protein
189
What is the largest family of cell-surface receptors?
G Protein coupled receptors (GPCR)
190
Where are GPCRs found?
All eucaryotes
191
How many GPCRs found in the sense of smell in humans? How many GPCRs found in the sense of smell in mice?
1. 700 in humans 2. 1,000 in mice
192
GPCR extracellular signaling molecules include what?
Proteins, small peptides, amino acid derivatives, and fatty acids
193
What is the structure of a GPCR?
7 transmembrane spanning domains
194
All GPCRs use G proteins to relay the signal into the what?
The cytosol
195
What is an orphan receptor?
A Receptor with no identified ligand
196
Approximately how many human GPCRs are orphan receptors?
~150 human GPCRs are 'orphan receptors'
197
What is this structure?
G-Protein-coupled receptor (GPCR)
198
What are GPCRs linked to via G-proteins?
Membrane localized enzymes or ion channels
199
G proteins are trimeric GTP-binding protein composed of what three subunits?
\_, _ and \_
200
What is linked to the cytoplasmic side of the plasma membrane via lipid attachments to the _ and _ subunits?
Trimeric protein complex
201
The \_-subunit has GTPase activity. Is it active or inactive when bound to GDP?
Inactive
202
The \_-subunit has GTPase activity. Is it active or inactive when bound to GTP?
Active
203
Activated GPCRs functions as a what to stimulate the exchange of GDP for GTP by the alpha subunit?
Guanine exchange factor
204
G-protein undergoes a conformational change with GTP binding that promotes what?
Interaction with downstream target proteins (membrane localized enzymes or ion channels)
205
Downstream activation is mediated by what?
Either the \_- or __ subunits
206
Activated G-proteins are released from GPCR which allows the receptor to do what?
Activate other G-proteins
207
\_-subunit association with its target protein stimulates its GTPase activity converting GTP to what?
GDP
208
What is the target protein for G-protein GAP (GTPase activating protein)?
Regulator of G protein signaling (RGS)
209
What is generated by ATP through the activity of membrane bound adenylyl cyclases?
cAMP
210
How do you increase cyclic AMP concentrations?
By increasing the activity of adenylyl cyclase over cellular phosphodiesterases
211
Cytosolic cAMP levels are typically low but can be elevated 20 fold with what?
Activation
212
cAMP can be converted to 5' monophosphate by what?
Cyclic AMP phosphodiesterases
213
How many adenylyl cyclase isoforms are there in mammals which are most regulated by G-proteins and Ca2+?
8
214
GPCRs that act by increasing cAMP are coupled to a stimultory G protein (Gs) which activate or inhibit adenylyl cyclase?
Activate
215
Inhibitory G proteins (Gi) activate or inhibit adenylyl cyclase?
Inhibit
216
What product is made at A?
cAMP
217
What product is made at B?
5'-AMP
218
How does the cholera toxin lead to elevated levels of cAMP levels? (3 steps)
1. Catalyzes the transfer of ADP ribose from NAD to the \_-subunit of Gs 2. Altered \_-subunit can not hydrolyzing its bound GTP 3. Generates a permenantly activated Gs: indefinitely stimulated adenylyl cyclase leads to elevated cAMP levels
219
How does the Pertussis Toxin work?
1. Modifiies the \_-subunit of Gi preventing interaction with receptors 2. Since the receptors function as GAPs, modified Gi proteins are never activated (i.e. no exchange of bound GDP for GTP) 3. Therefore, downstream targets are never activated
220
Which toxin (cholera or pertusis) promotes stable activation of Gs \_-subunit?
Cholera
221
Which toxin (cholera or pertusis) promotes stable inactivation of Gi \_-subunit?
Pertussis
222
Gs stimulated increases in cAMP generates differing intracellular responses based on what?
Cell type
223
Will increases in cAMP levels trigger the same intracellular response in the same cell regardless of the extracellular signal that triggered the increase?
Yes
224
Different cells may have a different intracellular response to increased what levels?
cAMP
225
What is a serine/threonine protein kinase that functions as a tetrameric protein complex?
PKA
226
What are the components of PKA?
2 Regulatory subunits and 2 Catalytic subunits
227
What subunit is used for PKA subcellular localization and binding to cAMP?
Regulatory subunit
228
What subunit is involved in target protein phosphorylation?
Catalytic subunit
229
What is the primary effector protein in cAMP mediated intracellular responses?
Protein kinase A, or PKA
230
Increases in cAMP leads to cAMP molecules binding to what subunits?
Regulatory subunits
231
cAMP bound induces a change in conformation promoting their release from the what?
The tetrameric complex
232
What are activated and able to phosphorylate substrate proteins?
Free catalytic PKA subunits
233
How many types of PKA are found in mammalian cells?
2
234
Where is PKA type I found?
Cytosol
235
PKA type II localized to what locations by its regulatory subunits?
1. Plasma membrane 2. Nuclear membrane 3. Mitochondrial outer membrane 4. Microtubules
236
PKA localization is mediated by its association with specific anchoring proteins called what?
AKAPs (A-kinase anchoring proteins)
237
A-kinase anchoring proteins (AKAPs) function to link PKA to what?
A component of the cytoskeleton, the membrane of an organelle or another signalling molecule
238
What binds to a G protein coupled receptor triggering a change in its conformation?
An extracellular signal
239
The GPCR functions as a GEF simulating the exchange of GDP for GTP by what subunit of its associated trimeric G-protein?
The \_-subunit
240
Activated G-protein (Gs) activates what?
Adenylyl cyclase
241
Activated adenylyl cyclase synthesizes what from ATP?
cAMP
242
cAMP binds to the regulatory subunit of PKA triggers what?
A change in conformation and its release from the catalytic subunits
243
Activated catalytic subunits of PKA translocate to the what?
Nucleus
244
In the nucleus, activated PKA phosphorylates what?
The CREB substrate protein
245
What is a gene regulatory protein that binds to specific DNA sequences called "cyclic AMP response element"?
CREB
246
Phosphorylated CREB recruits what?
CBP (CREB binding protein)
247
What is a transcriptional co-activator that functions to stimulate the transcription of target genes?
CBP
248
Phosphorylation of CREB is not required for what?
DNA binding
249
Phosphorylation of CREB is required for the recruitment of what?
CBP
250
Activated GPCRs function as a guanine exchange factor to stimulate the exchange of GDP for GTP by the alpha subunit.. Activated GPCRs can also activate what?
Phospholipase C
251
Phospholipase C cleaves plasma membrane bound
1. A membrane bound diacylglycerol 2. Water soluble inositol 1,4,5 triphosphate (IP3)
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phosphatidylinositol 4,5 bisphosphate (PIP2) into what two products?
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GPCR mediated activation of phospholipase C is through the activation of a what?
Gq protein
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What does diacylglycerol activate?
Protein kinase C
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What does inositol 1,4,5-triphosphate (IP3) release?
Ca3+ from the ER
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What is this?
Inositol 1,4,5-triphosphate (IP3)
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1. It diffuses throughout the cytosol 2. At the ER, it opens IP3 gated calcium release channels triggering release of stored calcium increases in intracellular calcium 3. It activates calcium sensitive proteins propagating the original signal
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What functions to activate protein kinase C?
Diacylglycerol
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activated PKC is dependent on the rise in cytosolic calcium levels triggered by IP3 as calcium binding to PKC promotes its relocation from the cytosol to where?
Plasma membrane
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Plasma membrane bound PKC interacts with phosphotidyl serine and diacylglycerol leading to what?
Its activation
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Activated PKC phosphorylates downstream target proteins propagating what?
The original signal
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What are the three steps in terminating IP3 mediated signaling?
1. Dephosphorylation of IP3 to IP2 by a lipid phosphatase 2. Phosphorylation of IP3 to IP4 by a lipid kinase 3. Removal of cytosolic calcium
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IP3 levels are decreased by either phosphorylation to generate what or dephosphorylation to generate what?
Phosphorylate: IP4 Dephosphorylate: IPs
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Cytosolic calcium levels are decreased through what?
Plasma membrane pumps and organellar pumps
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All eukaryotic cells contain what kind of pumps that moves calcium out of the cell
an ATP-dependent calcium pumps
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Cells that extensively utilize calcium signaling have an additional calcium pump in their plasma membrane, what is it?
The sodium driven calcium exchanger
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What two organelles contain calcium pumps that remove cytosolic calcium?
The ER and the mitochondria
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What kind of pump does the ER have?
ATP dependent calcium pump
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What pump is located in the inner membrane of the mitochondria and uses the energy stored in the proton gradient for the uptake of calcium
The mitochondrial calcium pump
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What is a key calcium binding protein that is found in all eukaryotic cells?
Calmodulin
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What is the structure of calmodulin?
Single polypeptide chain that folds into a dumbell shaped structure (2 globular ends linked through an \_-helix)
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How many calcium ion does calmodulin bind per globular head? How many total?
Binds 4 calcium ions; 2 per globular head
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When does calmodulin undergo a conformational change?
With calcium binding (activation)
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How many calcium ions must bind to trigger the conformational change in calmodulin?
2
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Activated calmodulin does what?
It binds to other target proteins activating those proteins
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What is the function of calmodulin?
It regulates enzymes and membrane transport proteins
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What is a large protein complex composed of 12 subunits?
CaM kinase II
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At the start of the reaction cycle CaM Kinase II is inactive with its amino terminal catalytic domain folded such that it interacts with what domain?
Its inhibitory domain
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An increase in cytosolic calcium levels activates calmodulin which binds to what?
CaM kinase II
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After calmodulin and CaM kinase II binding, a conformational change in CaM kinase II is induced partially activating what?
The kinase
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What activation requires autophosphorylation where the kinase activity of the catalytic domain phosphorylates the inhibitory domain of an adjacent CaM-kinase molecule?
Full CaM kinase II
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Can the fully activated form of CaM kinase II retain its kinase activity even if cytosolic calcium levels fall and calmodulin is released?
Yes
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Fully activated CaM kinase II can phosphorylate target substrate proteins long after what has been terminated?
The initial calcium signal has terminated
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Turning off CaM kinase II requires what to remove the activating phosphorylation on its regulatory domain?
Protein phosphatase
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What can G-proteins do to ion channels in the plasma membrane?
Activate or inactivate them
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If G-proteins activate or inactivate ion channels in the plasma membrane, what can they influence?
The membrane potential
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Give two kinds of regulation that G-proteins can have?
1. Phosphorylation of the ion channel (PKA, PKC or CaM-kinase) 2. Altering the levels of cyclic nucleotides
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Acetylcholine binds to plasma membrane receptors where?
On a muscle cell
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Acetylcholine binds to plasma membrane receptors on a muscle cell. What happens next?
A Gi protein is activated
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After the Gi protein is activated. What happens next?
The \_-subunit of the G protein inhibits adenylyl cyclase; the __ subunit opens plasma membrane K+ channels
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Opening of K+ channels leads to increased leakage of what? where?
Potassium ions out of the cell
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What is the end result of acetylcholine?
Muscle cell depolarization is more difficult reducing the rate and force of muscle contraction
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G proteins can also impact cyclic nucleotide gated channels by altering the levels of what?
Cyclic nucleotides (cGMP)
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What is the function of Gs?
Activates adenylyl cyclase; activates Ca2+ channels
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What is the function of Gi?
Inhibits adenylyl cyclase; activates K+ channels
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What is the function of Gq?
It activates phospholipase C-beta
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What are the three mechanisms of GPCR inactivation?
1. Receptor inactivation 2. Receptor sequestration 3. Receptor down-regulation
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Receptor alteration such that interaction with G proteins is lost?
Receptor inactivation
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Receptors are targeted for lysosomal destruction after internalization
Receptor down-regulation
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Receptors are moved to an intracellular compartment away from ligand
Receptor sequestration
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What alters the quantity of the receptor or the activity of the receptor?
Desensitization
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Inactivation depends on phosphorylation of the receptor by what?
PKA, PKC or a GPCR kinase
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Only what kind of receptors can be phosphorylated (and therefore undergo desensitization) as it is this receptor that activates these kinases
Activated receptors
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Phosphorylated GPCRs can interact with arrestin proteins and arrestin can prevent what? Blocking what?
GPCR interaction with downstream G-proteins blocking propagation of the signal.
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Arrestin binding can also promote what kind of endocytosis?
Clathrin-dependent
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What three things can happen to interalized receptors?
1. Dephosphorylated and returned back to the plasma membrane 2. Remain sequestered in endosomal compartments 3. Targeted to the lysosome for degradation
