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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
Q

GTPase-activating proteins (GAPs)

A

Drive G-proteins into off state by increasing rate of GTP hydrolysis

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26
Q

Guanine nucleotide exchange factors (GEFs)

A

activate GTP-binding proteins by promoting release of bound GDP (so a new GTP can bind)

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27
Q

How can the specificity of interactions between intracellular signaling molecules be enhanced?

Cells are crowded w signaling molecules that are related = noisy environ

A
  • 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
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28
Q

How do scaffold proteins form a signaling complex?

A

Bring groups of interacting signaling proteins together and hold them in close proximity
- rapid + effective activation, no cross-talk w/ other pathways

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29
Q

Assembly of a signaling complex on an activated receptor

A

Extracellular signal activates receptor –> signaling complex transiently forms around receptor (often cell-surface) and disassembles when extracellular signal is gone

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30
Q

Assembly of signaling complex on phosphoinositide docking sites

Phosphoinositide = modified phospholipid molecules (phosphorylated)

A

Receptor activation generates phosphoinositides in membrane next to receptor –> recruit intracellular signaling proteins to this region where they are activated
- phosphoinositides = docking sites

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31
Q

Modular interaction domains

Example

A

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

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32
Q

How do some signaling proteins function as adapters?

A

They link 2 other proteins together in a signaling pathway
- only have interaction domains (2+)

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33
Q

What do SH2 and SH3 domains bind to?

A
  • SH2: phosphorylated tyrosines
  • SH3: short, proline-rich aa sequences
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34
Q

What does the speed of a signaling response depend on?

A

the nature and turnover of intracellular signaling molecules

turnover = rate of destruction of molecules the signal affects

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35
Q

What kind of signal has a slow signaling response?

A

Signals that involve changes in gene expression and/or synthesis of new proteins = occur slowly

36
Q

What kind of signal has a rapid response?

A

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
Q

Ways that target cells can become adapted to extracellular signal

A
  • 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
Q

Why are the effects of protein kinases quickly reversed?

A

Like intracellular molecules, they continually undergo turnover
- phophorylation continually removed by phosphatases

38
Q

Positive vs negative feedback

A
  • positive: output (product) stimulates own production
  • negeative: output inhibits own production
39
Q

What occurs if positive feedback is strong enough?

A

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
Q

Adaptation or desensitization

A

Cells respond to changes in the strength of an input signal (rather than the amount of signal)

41
Q

What does adaptation to a signal require?

A

That a component of the signaling system generates a delayed inhibitory signal = reduce strength of output

42
Q

Ways that target cells can become adapted to extracellular signal

Delayed-feed forward loop

A

Activated receptor rapidly activates signaling response while initiating a slower inhibitory pathway

43
Q

Second messengers

A

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
Q

Types of secondary messengers

A
  • cyclic AMP (cAMP)
  • phosphoinositide
  • inositol phosphates
  • calcium
45
Q

What is the largest family of cell-surface receptors?

A

G-protein-coupled receptors (GPCRs)

46
Q

General structure of GPCRs

A
  • single polypeptide chain that goes thru the lipid bilayer 7 times
  • deep ligand binding site in core
47
Q

GTP-binding protein structure

G-protein

A

Heterotrimeric
- 3 subunits: alpha, beta, gamma

48
Q

How does a G-protein get activated?

A

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
Q

What helps a G protein bind to the plasma membrane of a cell?

A

the α and γ subunits are covalently attached to a lipid tail that binds to the membrane

50
Q

Which subunit of a G-protein binds to GDP/GTP?

A

Alpha subunit
- is also a GTPase that hydrolyzes GTP –> GDP

51
Q

What conformational change occurs in the α subunit of a G-protein to release GDP and bind to GTP?

A

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
Q

What enhances the GTPase activity of the α subunit of the G protein?

A

The binding of the subunit to a 2nd protein (target or regulator of G protein signaling, RGS)
- RGS acts as α-subunit GAPs

53
Q

Some G proteins regulate the production of cAMP

How is cyclic AMP synthesized?

A

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
Q

Some G proteins regulate the production of cAMP

How is cyclic AMP degraded?

A

cyclic AMP phosphodiesterases destroy cAMP by forming 5’-AMP
- cAMP is short lived + unstable (rapid synthesis balanced by rapid breakdown)

55
Q

Example of a signaling molecule that produces cAMP

A

serotonin –> acts through a GPCR and causes rapid rise in cAMP concentration

56
Q

What does cAMP mainly activate to exert its effects?

A

cyclic-AMP-dependent protein kinase (PKA, protein kinase A)
- mediates most of cAMP effects

57
Q

How does PKA regulate the activity of target proteins?

such as intracellular signaling proteins + effector proteins

A

By phosphorylating specific serines or threonines on target proteins

58
Q

Structure of the inactive state of PKA

A
  • 2 catalytic subunits
  • 2 regulatory subunits
59
Q

Activation of cyclic-AMP-dependent protein kinase (PKA)

A

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
Q

How can a rise in intracellular cAMP alter gene transcription?

A

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

  • CREB = CRE-binding protein (cyclic AMP response element), transcription regulator
  • CBP = CREB-binding protein, transcription coactivator (stimulates transcription of target genes)
61
Q

How do GPCRs exert their effects through G proteins that signal via phospholipids?

A

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
Q

2 products when phospholipase C-β cleaves phosphatidylinositol 4-5, biphosphate (phosphoinositide)

A
  • inositol 1,4,5-triphosphate (IP3)
  • diacyclglycerol

Signaling pathway splits into 2 branches afterwards

63
Q

Signaling pathway of IP3 (inositol 1,4,5-triphosphate)

A

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

IP3 receptor = calcium channel that is closed when IP3 is absent

64
Q

What opens the Ca2+ channel on the IP3 receptor?

IP3 receptor = transmembrane Ca2+ channel

A

IP3 and Ca2+ simultaneously binding

65
Q

Signaling pathway of diacylglycerol

A

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

  • PKC is Ca2+ dependent
66
Q

What activates PKC in the diacylglycerol signaling pathway?

A

Increase in Ca2+ (from IP3), diacylglycerol, and negatively charged phosphatidylserine (membrane phospholipid)

67
Q

What is the effect when diacyclglycerol is further cleaved?

A

Produces arachidonic acid
- can act as its own signal
- be used in synthesis of eicosanoids (biological activities such as pain + inflammation response)

68
Q

What causes cytosolic Ca2+ waves and oscillationsin a cell?

A

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
Q

Calmodulin

A
  • 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
Q

Structure of calmodulin

A
  • 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
Q

CaM-kinase ll

A
  • 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
Q

How is the CaM-kinase ll able to stay active even after the Ca2+ signal has decayed?

A

Adjacent kinase subunits can autophosphorylate each other
- activity remains until phosphotase removes autophosphorylation to shut kinase off

autophosphorylation
- traps the bound Ca2+/calmodulin complex
- converts enzyme into Ca2+-independent form

73
Q

What are the 2 domains of CaM-kinase ll

A
  • amino-terminal kinase domain
  • carboxyl-terminal hub domain

linked by regulatory segment

74
Q

How does smell depend on GPCRs?

A

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
Q

Response of a rod photoreceptor cell to light

A

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
Q

What keeps the cyclic-GMP-gated cation channels open in rods when there’s no light?

A

When cyclic GMP binds
- light induced activation = decreased cyclic GMP concentration so channels close

77
Q

Rhodopsin

A

Member of GPCR family that is activated by a photon of light

78
Q

The function of nitric oxide in smooth muscles.

A

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
Q

What causes nitric oxide production?

A

ACh binds to GPCR –> Ca2+ and IP3 are produced –> nitric oxide synthase activated

80
Q

Signaling through enzyme coupled receptors (RTKs)

A

activated receptor tyrosine kinases (RTKs) autophosphorylate –> phos. tyrosines are docking sites for signaling molecules –> proteins with SH2 domains bind to phos. tyrosines

81
Q

What enzyme mediates signaling done by most RTKs?

A

Monomeric GTPase - Ras

82
Q

Activation of RTKs

A

RTKs monomers bind to ligand –> dimerization, allows kinase domains to phosphorylate each other
- transautophosphorylation

83
Q

EGF receptor

A

Epidermal growth factor receptor
- type of enzyme-coupled receptor

84
Q

Activation of EGF Receptor

Epidermal Growth Factor Receptor

A

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
Q
A

Biol 445 - Cell Physiology (3 decks)

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