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Biol 445 - Cell Physiology > Lectures 3 to 5 - Cell Signaling > Flashcards

Lectures 3 to 5 - Cell Signaling Flashcards

1
Q

Contact-dependent intercellular signaling

A

Requires cells to be in direct contact
- extracellular signal bound to surface of signaling cells

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2
Q

How can a signal in contact-dependent signaling reach longer distances?

A

If the communicating cells extend thin, long processes that contact each other

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3
Q

Paracrine signaling

A

Signaling cells secrete local mediators into extracellular fluid
- impacts local environment

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4
Q

Synaptic signaling

A

Uses neurons that transmits electric signals and release neurotransmitters to contact target cell
- long distance signaling

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5
Q

Endocrine signaling

A

Depends on endocrine cells and secretion of hormones into blood
- long distance signaling

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6
Q

How are most signaling molecules released into the extracellular space?

for signaling in multicellular organisms

A
  • Mostly through exocytosis from signaling cell
  • Sometimes by diffusion from signaling cells membrane or being displayed on surface of cell (like contact-dependent signaling)
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7
Q

Types of receptors that bind a signaling molecule

A
  • cell-surface receptors
  • intracellular receptors
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8
Q

Cell-surface receptors

A

Bind extracellular signaling molecule (ligand) –> generate intracellular signals
- often transmembrane proteins

Most extracellular signals bind to receptors on cell surface

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9
Q

What kind of signal molecules generally bind to cell-surface receptors? To intracellular receptors?

A
  • cell-surface receptors: hydrophilic ligands (can’t cross plasma membrane directly)
  • intracellular receptors: hydrophobic + small ligands to cross plasma membrane (often bound to carrier proteins)
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10
Q

Intracellular receptors

A

Receptor proteins are located inside the cell and ligands need to diffuse across membrane to bind

receptors usually in cytosol or nucleus

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11
Q

How do cells respond differently to combinations of extracellular signals?

A

Combinations of signals differ based on the message they are trying to communicate
- ex. signals differ when a cell wants to promote proliferation vs cell death (apoptosis = deprived of survival signals)

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12
Q

Example of how a signal molecule can have different effects on different types of target cells.

A

Acetylcholine
- heart pacemaker cell: decrease firing rate
- salivary glands: stimulate saliva production
- skeletal muscle: causes cell contraction

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13
Q

What are signal transducers?

A

Cell-surface receptors that convert an extracellular ligand-binding event into intracellular signals to alter cell behavior.

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14
Q

How does acetylcholine cause different effects even though the acetylcholine receptors are the same on 2 different cells?

A

The different effects are due to differences in the activated intracellular signaling proteins, effector proteins, and genes

signals are interpreted differently

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15
Q

What are the 3 major classes of cell-surface receptor proteins?

A
  • ion-channel-coupled receptors
  • G-protein-coupled receptors
  • enzyme-coupled receptors

Category defined by their transduction mechanism

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16
Q

Type of cell-surface receptor protein

Ion-channel-coupled receptors

A

Involved in rapid synaptic signaling between nerve cells and other electrically excitable target cells (muscle)
- mediated by neurotransmitters that open/close an ion channel

aka transmitter-gated ion channels or ionotropic receptors

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17
Q

Type of cell-surface receptor protein

G-protein-coupled receptors

A

Indirectly regulate target protein by using GTP-binding proteins
- mediate interaction btwn receptor and target protein

target protein = generally enzyme or ion channel

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18
Q

Type of cell-surface receptor protein

Enzyme-coupled receptors

A

Function as enzymes or associate directly with the enzymes they activate
- mostly protein kinases (or associated)

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19
Q

Classes of molecular switches

A
  • protein kinases: serine/threonine, tyrosine kinases
  • GTP-binding proteins: G-proteins, manomeric GTPases
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20
Q

Types of GTP-binding proteins

G proteins

A

Relay signals from G-protein-coupled receptors

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21
Q

Types of GTP-binding proteins

Monomeric GTPases

A

Relay signals from many classes of cell-surface receptors

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22
Q

Why is the activation/inactivation process slow for GTP-binding proteins when other proteins are absent?

A

Because regulatory proteins are used to accelerate the processes –> govern the activation state of G-proteins

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23
Q

What determines the on/off state for GTP-binding proteins?

A
  • GTP bound = on
  • GDP bound = off
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24
Q

What regulates GTP-binding proteins?

A
  • GTPase activating proteins (GAPs)
  • guanine nucleotide exchange factor (GEFs)
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25
GTPase-activating proteins (GAPs)
Drive G-proteins into off state by increasing rate of GTP hydrolysis
26
Guanine nucleotide exchange factors (GEFs)
activate GTP-binding proteins by promoting release of bound GDP (so a new GTP can bind)
27
How can the specificity of interactions between intracellular signaling molecules be enhanced? | Cells are crowded w signaling molecules that are related = noisy environ
- localize molecules in the same part of the cell to promote interactions w/ each other --> involve **scaffold proteins** - intracellular signals have high affinity + specificity for their correct partner
28
How do scaffold proteins form a signaling complex?
Bring groups of interacting signaling proteins together and hold them in close proximity - rapid + effective activation, no cross-talk w/ other pathways
29
Assembly of a signaling complex on an activated receptor
Extracellular signal activates receptor --> signaling complex transiently forms around receptor (often cell-surface) and disassembles when extracellular signal is gone
30
Assembly of signaling complex on phosphoinositide docking sites | Phosphoinositide = modified phospholipid molecules (phosphorylated)
Receptor activation generates phosphoinositides in membrane next to receptor --> recruit intracellular signaling proteins to this region where they are activated - phosphoinositides = docking sites
31
Modular interaction domains | Example
Mediate interactions between intracellular signaling proteins - can connect protein to additional signaling pathways - binds to particular structural motif in another protein/lipid | SH2 and SH3 domains
32
How do some signaling proteins function as adapters?
They link 2 other proteins together in a signaling pathway - only have interaction domains (2+)
33
What do SH2 and SH3 domains bind to?
- SH2: phosphorylated tyrosines - SH3: short, proline-rich aa sequences
34
What does the speed of a signaling response depend on?
the nature and turnover of intracellular signaling molecules | turnover = rate of destruction of molecules the signal affects
35
What kind of signal has a slow signaling response?
Signals that involve changes in gene expression and/or synthesis of new proteins = occur slowly
36
What kind of signal has a rapid response?
Changes in cell movement, secretion, or metabolism occur quickly (no changes in gene expression) | bc it may just involve a quick phosphorylation of effector proteins
36
Ways that target cells can become adapted to extracellular signal
- negative feedback - delayed-feed forward - receptor inactivation - recepter sequestration (endosome) - receptor destruction (lysosome) | receptor mechanisms can all be connected in a series of steps
37
Why are the effects of protein kinases quickly reversed?
Like intracellular molecules, they continually undergo turnover - phophorylation continually removed by phosphatases
38
Positive vs negative feedback
- positive: output (product) stimulates own production - negeative: output inhibits own production
39
What occurs if positive feedback is strong enough?
All-or-none response - the system has a high level of activation and can be self-sustaining even when the signal strength drops - transient signal can induce long-term changes in cells | (+) feedback is moderate strength, sigmoidal response is generated
40
Adaptation or desensitization
Cells respond to changes in the strength of an input signal (rather than the amount of signal)
41
What does adaptation to a signal require?
That a component of the signaling system generates a delayed inhibitory signal = reduce strength of output
42
# Ways that target cells can become adapted to extracellular signal Delayed-feed forward loop
Activated receptor rapidly activates signaling response while initiating a slower inhibitory pathway
43
Second messengers
Small molecules or ions that relay signals from cell-surface receptors to effector proteins | Diffuse rapidly from source --> bind to target proteins to alter behav.
44
Types of secondary messengers
- cyclic AMP (cAMP) - phosphoinositide - inositol phosphates - calcium
45
What is the largest family of cell-surface receptors?
G-protein-coupled receptors (GPCRs)
46
General structure of GPCRs
- single polypeptide chain that goes thru the lipid bilayer 7 times - deep ligand binding site in core
47
GTP-binding protein structure | G-protein
Heterotrimeric - 3 subunits: alpha, beta, gamma
48
How does a G-protein get activated?
signal molecule binds to GPCR --> GPCR acts like a GEF and induces the α subunit to release GDP --> GTP binds --> conf change in α subunit and G is released from receptor + Gβγ pair --> both interact with various targets
49
What helps a G protein bind to the plasma membrane of a cell?
the α and γ subunits are covalently attached to a lipid tail that binds to the membrane
50
Which subunit of a G-protein binds to GDP/GTP?
Alpha subunit - is also a GTPase that hydrolyzes GTP --> GDP
51
What conformational change occurs in the α subunit of a G-protein to release GDP and bind to GTP?
The AH domain of α subunit moves outwards --> opens GTP-binding site to dissociate GDP --> GTP binding closes site --> conf change dissociates α from βγ
52
What enhances the GTPase activity of the α subunit of the G protein?
The binding of the subunit to a 2nd protein (target or regulator of G protein signaling, RGS) - RGS acts as α-subunit GAPs
53
# Some G proteins regulate the production of cAMP How is cyclic AMP synthesized?
synthesized from ATP - adenylyl cyclase catalyzes the rxn by removing 2 phosphate groups as pyrophosphate (PP) from ATP --> pyrophosphatase converts PP to phosphate (P+P) | Gs activates adenylyl cyclase
54
# Some G proteins regulate the production of cAMP How is cyclic AMP degraded?
cyclic AMP phosphodiesterases destroy cAMP by forming 5'-AMP - cAMP is short lived + unstable (rapid synthesis balanced by rapid breakdown)
55
Example of a signaling molecule that produces cAMP
serotonin --> acts through a GPCR and causes rapid rise in cAMP concentration
56
What does cAMP mainly activate to exert its effects?
cyclic-AMP-dependent protein kinase (PKA, protein kinase A) - mediates most of cAMP effects
57
How does PKA regulate the activity of target proteins? | such as intracellular signaling proteins + effector proteins
By phosphorylating specific serines or threonines on target proteins
58
Structure of the inactive state of PKA
- 2 catalytic subunits - 2 regulatory subunits
59
Activation of cyclic-AMP-dependent protein kinase (PKA)
cAMP binds to regulatory subunits (2) --> conf change dissociating from catalytic subunits --> catalytic subunits activated to phosphorylate targets **- 2+ cAMP molecules required to bind for dissociation of catalytic subunits**
60
How can a rise in intracellular cAMP alter gene transcription?
signaling molecule activates GPCR --> adenylase cyclase is activated, [cAMP] increases --> activates PKA, catalytic subunits released into nucleus --> phosphorylate CREB on a single serine --> P CREB recruits CBP = short cAMP signal turned into long-term change in cell ## Footnote - CREB = CRE-binding protein (cyclic AMP response element), transcription regulator - CBP = CREB-binding protein, transcription coactivator (stimulates transcription of target genes)
61
How do GPCRs exert their effects through G proteins that signal via phospholipids?
G protein (Gq) activates plasma membrane bound enzyme, phospholipase C-β --> phospholipase cleaves phosphoinositide --> inositol 1,4,5-triphosphate and diacylglcerol generated --> signaling pathway splits into 2 branches | phosphoinositide = in inner half of lipid bilayer membrane
62
2 products when phospholipase C-β cleaves phosphatidylinositol 4-5, biphosphate (phosphoinositide)
- inositol 1,4,5-triphosphate (IP3) - diacyclglycerol | Signaling pathway splits into 2 branches afterwards
63
Signaling pathway of IP3 (inositol 1,4,5-triphosphate)
Leaves plasma membrane and goes into ER to bind IP3 receptors --> conf change, Ca2+ binding site exposed --> Ca2+ channel opened, Ca2+ binds to more IP3-bound receptors --> widespread channel opening, large increase of Ca2+ --> Ca2+ propagates signal and influences Ca2+-sensitive proteins ## Footnote IP3 receptor = calcium channel that is closed when IP3 is absent
64
What opens the Ca2+ channel on the IP3 receptor? | IP3 receptor = transmembrane Ca2+ channel
IP3 and Ca2+ simultaneously binding
65
Signaling pathway of diacylglycerol
Activates protein kinase C (PKC) --> Ca2+ increase from IP3 causes PKC to move from cytosol to face of plasma membrane --> PKC activated (from combo of Ca2+, diacylglycerol, - membrane phospholipid) --> phosphorylate target proteins | diacylglycerol remains bound to plasma membrane ## Footnote - PKC is Ca2+ dependent
66
What activates PKC in the diacylglycerol signaling pathway?
Increase in Ca2+ (from IP3), diacylglycerol, and negatively charged phosphatidylserine (membrane phospholipid)
67
What is the effect when diacyclglycerol is further cleaved?
Produces arachidonic acid - can act as its own signal - be used in synthesis of eicosanoids (biological activities such as pain + inflammation response)
68
What causes cytosolic Ca2+ waves and oscillationsin a cell?
Positive + negative feedback - Positive: IP3 and Ca2+ open a Ca2+ channel --> opens more IP3 receptors, more Ca2+ release - Negative: high Ca2+ concentration --> Ca2+ inactivates IP3 receptors | Ca2+ channels go into refractory period after IP3 receptors inactivated
69
Calmodulin
- found in all euk cells - intracellular Ca2+ receptor - single polyp chain, 4 Ca2+ binding sites - 2+ Ca2+ ions must bind before calmodulin goes into active conformation --> folds around peptide portion of target protein
70
Structure of calmodulin
- 2 globular ends connected by alpha helix (2 Ca2+ binding sites on each globular end) | alpha helix allows protein to have many diff conformatinos
71
CaM-kinase ll
- 12 copies of enzyme into stacked ring pairs --> helps enzyme stay active even after Ca2+ signal is gone - serves as memory trace of a prior Ca2+ pulse | CaM-kinases = Ca2+-calmodulin dependent kinases
72
How is the CaM-kinase ll able to stay active even after the Ca2+ signal has decayed?
Adjacent kinase subunits can autophosphorylate each other - activity remains until phosphotase removes autophosphorylation to shut kinase off ## Footnote autophosphorylation - traps the bound Ca2+/calmodulin complex - converts enzyme into Ca2+-independent form
73
What are the 2 domains of CaM-kinase ll
- amino-terminal kinase domain - carboxyl-terminal hub domain | linked by regulatory segment
74
How does smell depend on GPCRs?
olfactory receptors are GPCRs that are located on cilia of olfactory neurons --> odor binds --> G(olf) protein is activated and activates adenylyl cyclase --> cAMP increases --> cAMP-gated cation channels open and Na+ influx --> nerve impulse initiated (travels to brain)
75
Response of a rod photoreceptor cell to light
rhodopsin molecules in outer-segment of rods absorb photon of light --> absorption closes cation channels in membrane (activated rhodopsin activate c-GMP phosphodiesterase) --> hyperpolarization, reduces neurotransmitter release
76
What keeps the cyclic-GMP-gated cation channels open in rods when there's no light?
When cyclic GMP binds - light induced activation = decreased cyclic GMP concentration so channels close
77
Rhodopsin
Member of GPCR family that is activated by a photon of light
78
The function of nitric oxide in smooth muscles.
Relaxation of smooth muscle in the walls of blood vessels - ACh stimulates NO synthesis --> diffuses out of cell its produced in and goes into neighbor smooth muscle cells --> muscle relaxation and vessel dilation (due to cyclic GMP production) | - acts locally due to short half life
79
What causes nitric oxide production?
ACh binds to GPCR --> Ca2+ and IP3 are produced --> nitric oxide synthase activated
80
Signaling through enzyme coupled receptors (RTKs)
activated receptor tyrosine kinases (RTKs) autophosphorylate --> phos. tyrosines are docking sites for signaling molecules --> proteins with SH2 domains bind to phos. tyrosines
81
What enzyme mediates signaling done by most RTKs?
Monomeric GTPase - Ras
82
Activation of RTKs
RTKs monomers bind to ligand --> dimerization, allows kinase domains to phosphorylate each other - transautophosphorylation
83
EGF receptor
Epidermal growth factor receptor - type of enzyme-coupled receptor
84
Activation of EGF Receptor | Epidermal Growth Factor Receptor
EGF binds to EGFR --> conformational change, dimerization of external domains --> causes internal kinase domains to asymmetrically dimerize, 1 domain pushes against other --> conformational change in receiver domain so it phosphorylates multiple tyrosines in both receptors (C term tail) --> docking sites for signal proteins
85

Biol 445 - Cell Physiology (3 decks)

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