3 Flashcards
1
Q
What types of molecule act as signals?
A
Amino acids and their derivatives, steroids, peptides & proteins, gases
2
Q
example of amino acid signaler
A
Glutamic acid - the major excitatory neurotransmitter
3
Q
example of amino acid derivative signaler
A
- GABA (glutamic acid) - the major inhibitory neurotransmitter.
- Epinephrine (tyrosine) - hormone that increases blood glucose
4
Q
example of steroid signaler
A
Estrogens, testosterone (derived from cholesterol)
5
Q
example of peptide and protein signaler
A
- insulin - hormone that reduces blood glucose
- glucagon - hormone that increases blood glucose
6
Q
example of gas signaler
A
nitrous oxide - vasodilator
7
Q
contact-dependent cell communication
A
- cell junctions - gap junctions (animal) and plasmodesmata (plant) are cell junctions that
allow molecules to pass readily between adjacent cells without crossing plasma membranes - cell-cell recognition - Two cells in an animal may communicate by direct interaction between molecules protruding from their surfaces (e.g. cell adhesion)
8
Q
local signaling
A
- Released molecule acts locally on cells in
the near vicinity by binding to specific
receptors. - Local mediator must act quickly on nearby
cells before being destroyed by
extracellular enzymes or immobilized by
extracellular matrix. - Example: Growth factors released from
one cell to stimulate the growth of nearby
cells. - Autocrine, paracrine and synaptic
9
Q
paracrine signaling
A
the release of a chemical signal (local regulator) from one cell that is detected by and
alters the function of a closely located cell.
- secretory vesicle containing local regulator travels towards plasma membrane and empties it contents outside of the cell
- local regulator diffuses through extracellular fluid and reaches target cell
10
Q
autocrine signaling
A
the release of a chemical signal from one cell that is detected by and
alters the function of the same cell. A specialized signaling mechanism that allows
the signaling cell to monitor the amount of signal that it is releasing, for example.
11
Q
synaptic (neural) signaling
A
- communication between a nerve cell and a target cell following an electrical signal carried down the neuronal axon. The release of neurotransmitters activates receptors on the target cell.
- Example: motor neuron activation of a skeletal muscle.
1. electrical signal triggers release of neurotransmitter (same vesicle process)
2. neurotransmitter diffuses across synapse
12
Q
endocrine (hormonal) signaling
A
- LONG-dist: Useful for communication from a distance—and can affect many cells at once.
- Specialized endocrine cells secrete hormones into body fluids, often blood, where they travel to target cells. Hormones reach virtually all body cells, but are bound only by some cells.
- ex: insulin release from pancreas cells
13
Q
Cell-cell signaling via signaling molecules fall into two classes
A
cell-surface and intracellular receptors
14
Q
cell-surface receptors
A
- involves water-soluble (hydrophilic) molecules such as insulin; since they’re water-soluble, they act act receptors in the plasma membrane
1. the molecule is released by the secretory cell, sometimes into blood vessel
2. molecule leaves blood vessel and binds to cell-surface receptor protein
3. after binding, a cytoplasmic response is triggered OR gene regulation is triggered, which in turn leads to cytoplasmic response
15
Q
intracellular receptors
A
- involves lipid-soluble (hydrophobic) molecules such as steroid hormones; since they’re lipid-soluble, they pass through cell membranes and act at receptors in nucleus or cytoplasm
1. molecule is released by secretory cell, sometimes into blood vessel, where it sometimes binds to transport protein
2. molecule leaves and enters cell (w/o transport protein), where it binds to receptor protein in nucleus or cytoplasm
3. binding leads to gene regulation, which triggers cytoplasmic response
16
Q
three stages to the signaling process in the target cell
A
- Reception: is the target cell’s detection of a
signaling molecule coming from outside the cell, which occurs when the signaling molecule binds to a receptor protein located at the cell’s surface or inside the cell. - Transduction: The binding of the signaling molecule
changes the receptor protein in some way, initiating the
process of transduction. Transduction converts the signal to a form that can bring about a specific cellular response. It sometimes occurs in a single step but more often requires a sequence of changes in a series of different molecules—a signal transduction pathway. The molecules in the pathway are often called relay molecules. involves 1) alteration of enzyme function 2) alteration of gene expression - Response: the transduced signal triggers a specific cellular response
17
Q
ligand
A
The signaling molecule is complementary in shape to a specific site on the receptor and attaches there, like a key in a
lock or a substrate in the catalytic site of an enzyme. The signaling molecule behaves as a ligand, the term for a molecule that specifically binds to another molecule, often a
larger one. Ligand binding generally causes a receptor protein to undergo a change in shape.
18
Q
Signal transduction pathways
A
cascades of intracellular events. They are
triggered by the binding of the ligand to its specific receptor.
19
Q
Signal transduction pathways advantages
A
1) allows the signal to be amplified. If the end result is the activation of a
metabolic enzyme, it is not very efficient to have a one receptor activating one
enzyme. Much more efficient if the signal is amplified.
2) allows one signal to diverge and control a range of cellular processes.
3) allows other signals to control the cascade.
20
Q
second messengers
A
- Many signaling pathways also involve small, nonprotein, water-soluble molecules or ions called second messengers. (This term is used because the pathway’s “1st messenger” is considered to be the ligand.) Because second messengers are small and water-soluble, they can readily spread throughout the cell by diffusion.
- act to trigger the transduction cascade.
• Their intracellular concentrations are controlled by receptor activation.
• They function as intermediaries between the receptor and the cascade.
• Cells have three principal second messengers:
1. Cyclic adenosine monophosphate (cyclic AMP)
2. Calcium ions (Ca2+)
3. Inositol Trisphosphate (IP3)
21
Q
fast signaling
A
Fast responses are due to changes to protein function.
Example: modification of the cytoskeleton.
22
Q
slow signaling
A
- mins to hrs
- Slow responses are due to changes in the rate or type of protein synthesis. These changes require changes in gene transcription or translation. Require synthesis of new proteins
- ex: modifications to rate of cell growth
23
Q
kinase
A
- An enzyme that transfers phosphate groups from ATP
onto another molecule, usually a protein, and often another enzyme - The phosphate group will change the conformation of the protein and alter its function (either activating or inactivating).
- Phosphate groups can be removed by phosphatase enzymes; phosphatases undo what kinases do.
24
Q
The same signaling molecule can have different effects on
different target cells.
A
- The specificity of the effect is in the
nature of the receiving cell not in the
nature of the signaling molecule. - ex: effects of ACh (acetylcholine) on skeletal, heart, salivary gland cells
25
ACh
- In skeletal muscle, ACh binds to a
receptor that cause muscle contraction. In heart muscle, the same signaling molecule, ACh, binds to a different
receptor resulting in a decrease in the contraction (exactly the opposite of its effect on skeletal muscle).
- Sometimes, the signaling molecule binds to the same receptor on different cells and triggers different responses. On salivary gland cells ACh causes the cell to secrete saliva. The
receptor on this cell is the same as on the heart muscle.
26
ion channel-coupled receptors steps
1. When the ligand binds to the receptor and the
gate opens, specific ions can flow through the channel
and rapidly change the concentration of that particular ion inside the cell. This change may directly affect the activity of the cell in some way.
2. When the ligand dissociates from this receptor, the gate closes and ions no longer enter the cell.
27
ion channel coupled receptors are very important in
- the nervous system; they're aka transmitter-gated ion channel. For example, the neurotransmitter molecules released at a synapse between two nerve cells bind as
ligands to ion channels on the receiving cell, causing the
channels to open. Ions flow in (or, in some cases, out), triggering an electrical signal that propagates down the length of the receiving cell (transiently change the ion permeability of the plasma membrane)
- involves 2nd messenger Ca2+
28
G protein
- Loosely attached to the cytoplasmic side of the membrane, the G protein functions as a molecular switch that is either on or off, depending on which of two guanine nucleotides is attached, GDP or GTP. When GDP is bound to the G protein, as shown above, the G protein is inactive.
- The G protein is membrane delimited: it is associated with the membrane and can move along it but doesn’t leave it.
29
actors in GPCRs
1. transmembrane receptor
2. G protein
3. another transmembrane protein that's an enzyme
30
GTPase
The G-protein is also a GTPase. This means that it
converts GTP (guanosine triphosphate) back into GDP
(guanosine diphosphate) by cleaving off the terminal
phosphate. When the G-protein has GDP bound (as
opposed to GTP), it is inactive and so no longer activates
the enzyme and the response is terminated
- The GTPase
function of the G protein allows the pathway to shut down rapidly
when the signaling molecule is no longer present.
31
GPCR steps
1. Signaling molecule binds to extracellular side of receptor, activating it and changing its shape. Its cytoplasmic side then binds an inactive G protein, causing a GTP to displace the GDP. This activates the G protein.
2. The activated G protein dissociates from the receptor, diffuses along the membrane, and then binds to an enzyme, altering the enzyme’s shape and activity. Once activated, the enzyme can trigger the next step leading to a cellular response.
3. The G protein's GTPase function hydrolyzes its bound GTP to GDP. Now inactive again, the G protein leaves the enzyme, which returns to its original state. The G protein is now available for reuse.
32
cAMP
- cyclic adenosine monophosphate
- Many G-protein signaling pathways involve production of the second messenger cAMP.
- Adenylyl cyclase (the 'enzyme' actor) catalyzes a cyclization reaction that removes 2 phosphates from ATP, forming cAMP.
- cAMP phosphodiesterase hydrolyzes cAMP into 5’-AMP. This is the 3rd way the process can be terminated. (The first two are unbinding of the signaling molecule and the GTP to GDP conversion by the G protein.)
33
phosphorylation cascade
1. relay molecule activates protein kinase 1
2. Active protein kinase 1 transfers a phosphate from ATP to an inactive molecule of protein kinase 2, thus activating kinase 2
3. Active protein kinase 2 then catalyzes the phosphorylation (and activation) of protein kinase 3.
4. Finally, active protein kinase 3 phosphorylates a
protein that brings about the cell‘s response to the signal.
5. Enzymes called protein phosphatases (PP) catalyze the removal of the phosphate groups from the proteins, making them inactive and available for reuse
34
importance of the phosphorylation-dephosphorylation
| system
- By dephosphorylating and thus inactivating protein
kinases, phosphatases provide the mechanism for turning off the signal transduction pathway when the initial signal is no longer present.
- Phosphatases also make the protein kinases available for reuse, enabling the cell to respond again to an extracellular signal.
- acts as a molecular switch in the cell, turning activities on or off, or up or down, as required. At any given moment, the activity of a protein regulated by phosphorylation depends on the balance in the cell between active kinase molecules and active phosphatase molecules.
35
GCPR amplification example: reception
Binding of epinephrine to G protein-coupled receptor (1 molecule)
36
GCPR amplification example: transduction
GAAPPG
1. inactive --> active G protein (10^2 molecules)
2. inactive --> active adenylyl cyclase (10^2)
3. ATP --> cAMP (10^4)
4. inactive --> active protein kinase A (10^4)
5. inactive --> active phosphorylase kinase (10^5)
6. inactive --> active glygocen phosphorylase (10^6)
37
GCPR amplification example: response
glygocen --> glucose 1-phosphate (10^8)
38
activation of a specific gene by a growth factor
1. reception: growth factor binds to receptor
2. transduction: phosphorylation cascade
3. response: once phosphorylated, the last kinase in the sequence enters the nucleus and there activates a gene-regulating protein, a transcription factor, by binding a phosphate to it --> factor binds to DNA --> mRNA
39
IP3
inositol trisphosphate, a 2nd messenger
40
Calcium and IP3 in signaling pathways
1. A signaling molecule binds to a receptor, leading to activation of phospholipase C
2. Phospholipase C cleaves a plasma membrane phospholipid called PIP2 into DAG and IP3. (DAG functions as a 2nd messenger in other pathways)
3. IP3 quickly diffuses through cytosol and binds to an IP3-gated Ca channel in ER membrane, causing it to open
4. Ca2+ flow out of ER (down concentration gradient), raising Ca2+ level in cytosol.
5. the Ca2+ activate the next protein (e.g. calmodulin) in one or more signaling pathways
41
where is Ca2+ concentration low
The Ca2+ concentration in the cytosol is usually much lower than in the extracellular fluid, ER, interior of mitochondrion
42
Calcium as a Second Messenger
- To terminate Ca2+ signaling, it is removed from the cytoplasm by Ca2+ pumps. To do so, ATP is used to move Ca2+ against its concentration gradient (active
transport) .
- Ca2+ can be pumped to three places:
1) Out of the cell
2) Into mitochondria
3) Into smooth ER
43
enzyme-coupled receptors
- Enzyme-coupled receptors are transmembrane proteins w/ ligand-binding part on the extracellular face and their catalytic site on the intracellular face.
- Almost all enzyme-linked receptors are protein
kinases: proteins that phosphorylate other proteins.
- Kind of like a hybrid between a receptor (like a GPCR) and an enzyme (like adenylyl cyclase).
- Binding of a signal activates the catalytic
domains of the receptors.
44
RTK structure
- Receptor tyrosine kinases; common type of enzyme-coupled receptor
- pair of monomers
- extracellular ligand-binding site
- alpha helix spanning the membrane
- intracellular tail containing multiple tyrosines
45
RTK steps
1. The binding of a signaling molecule (such as a growth factor) causes 2 receptor monomers to associate closely with each other, forming a complex known as a dimer (dimerization).
2. Dimerization activates the tyrosine kinase region of each monomer; the 2 monomers phosphorylate each other at the tyrosines, activating the receptor.
3. Now that the receptor is fully activated, it is recognized by specific relay proteins inside the cell. Each such protein binds to a specific phosphorylated tyrosine, undergoing a resulting structural change that activates the bound protein.
4. Each activated protein triggers a transduction pathway, leading to a cellular response.
46
insulin receptor structure
- set of monomers that dimerizes when activated
- beta subunit that spans the membrane
- alpha subunit bound to beta subunit only at extracellular portion; has ligand-binding sites
47
insulin receptor steps
1. insulin, the ligand, binds to site on alpha subunit
2. the receptors are activated and dimerize, phosphorylating each other
3. this in turn activates the insulin response substrate (by phosphorylating it), leading to a cellular response (such as putting more glucose transporters into the membrane)
48
result of insulin receptor steps
signal transduction --> recruit vesicles that contain glucose transporters (such as GLUT4) and put them in the membrane to allow glucose to enter the cell. ppl w/ t2 diabetes have trouble recruiting these glucose receptors into the membrane.
