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Molecular & Cellular Mechanisms > Receptors and Cell Signaling > Flashcards

Receptors and Cell Signaling Flashcards

1
Q

What are the types of signaling?

A

Endocrine, paracrine, autocrine, juxtacrine

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2
Q

Endocrine signaling

A
  1. Long distance signaling
  2. Signal is made, goes to blood stream and targets distant cells
  3. FREELY DIFFUSIBLE signals that are LONG LASTING.
  4. Steroid hormones (epinephrine, leptin)
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3
Q

Paracrine signaling

A
  1. Acts locally
  2. Affects cells that are nearby, do not freely diffuse
  3. Short lived
  4. Neurotransmitters
  5. Generally don’t want to go into bloodstream.
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4
Q

Autocrine signaling

A
  1. Cells respond to signals they release or release to cells of the same type
  2. Cells secrete signal that feeds back and binds to a receptor on its own surface (has its own receptors)
  3. Ligands are not as long lasting
  4. Growth factors in cancer, chemokines,
  5. Important for immune response, homeostasis of tissues.
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5
Q

Juxtacrine (Direct cell) signaling

A
  1. Molecule stays attached to signaling cell and binds to a receptor on adjacent target cell.
  2. PHYSICAL CONTACT between cells.
  3. Immune cells, Antigen presenting cells to T-cells
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6
Q

Epinephrine on glucose metabolism

A

Encourages breakdown of glycogen by promoting glucose secretion

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7
Q

Glucagon on glucose metabolism

A

Elevates blood glucose by promoting glycogen breakdown and gluconeogenesis

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8
Q

Cortisol on glucose metabolism

A

If glycogen stores are depleted, stimulates gluconeogenesis by inducing transcription of enzymes in that pathway

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9
Q

Insulin on glucose metabolism

A

Lowers blood glucose by promoting glycolysis and inhibiting gluconeogenesis

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10
Q

Deficiency in insulin

A

Elevated blood glucose

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11
Q

Types of signaling molecules (2)

A

lipophilic and hydrophilic

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12
Q

Lipophilic signaling molecules

A
  1. Lipid soluble molecules that diffuse freely through lipid bilayer of PM
  2. HYDROPHOBIC, BIND INTRACELLULARLY
  3. Steroid hormones, retinoids, thyroid hormones
  4. Not water soluble, need carrier proteins
  5. Long half-life, administered daily
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13
Q

Lipophilic receptors

A
  1. Binding leads to alterations in gene transcription
  2. Cytoplasmic receptors exist as inactive complex w/ HSP 90, when binding, complex disassociates from HSP
  3. Translocates to nucleus and binds to DNA sequence (HRE) in the promoter region
  4. Nuclear receptors – present in nucleus already bound to DNA
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14
Q

Hydrophilic signaling molecules

A
  1. Receptor on surface, triggers activation of signaling events downstream from signal/molecule complex
  2. Small, derived from amino acids, lipid metabolism or small polypeptides (glucagon, insulin)
  3. Do not need carrier protein
  4. Most signaling molecules are hydrophilic and require cell-surface receptors
  5. Short half-life, administer when needed (epinephrine)
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15
Q

Hydrophilic receptors

A
  1. Transmembrane proteins that undergo conformational change when binded to
  2. Cascade of signaling events
  3. GPCR - 7 alpha-helical transmembrane proteins
  4. Mediated by trimeric G-proteins, effector proteins and second messengers
  5. Receptor tyrosine kinases - single alpha helical transmembrane proteins
  6. Use enzymatic activity to initiate cascade of events mediated by monomeric G-proteins and kinases
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16
Q

Lipophilic medication half-life

A

Hours to days, administered daily

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17
Q

Hydrophilic medication

A

Like epinephrine, used to treat allergic reactions. Administer when needed.

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18
Q

GPCR Structure

A
  1. Extracellular domain with binding site for specific signaling molecule
  2. Transmembrane domain of 7 a-helices
  3. Intracellular domain that interacts with trimeric G-protein (a, b, gamma)
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19
Q

GPCR Sequence

A
  1. Signaling molecule binds in extracellular domain
  2. Conformational change in protein
  3. Intracellular domain activates trimeric G-protein (exchange GDP for GTP)
  4. G-protein is activated and interacts with membrane bound effector protein
  5. Signal termination (dissociation of signal from receptor, G-protein inactivation, reduction of second messenger, etc)
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20
Q

Trimeric G-protein (a, b, gamma) states of activation

A
  1. Inactive G-protein: GDP-Ga (attached to beta/gamma)
  2. Active: GDP exchanged for GTP via GEF, Ga-GTP separates from beta, gamma
  3. Inactivation: intrinsic GTPase activity hydrolyzes GTP to GDP + Pi, accelerated by GAP
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21
Q

GEF and GAP

A
  1. GEF is a protein that activates G-proteins by exchanging GDP for GTP
  2. GAP accelerates hydrolyzing activity of GTP to GDP + Pi
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22
Q

Different GPCRs interact with different types of G-proteins

A

Gs, Gi, Gq, Gt

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23
Q

Effector proteins

A

Membrane bound enzymes that catalyze reactions to produce second messengers (cAMP, cGMP, DAG, IP3)

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24
Q

Common GPCR Signaling Pathways

A
  1. Signaling via Gs and Gi modulates adenylate cyclase and cAMP
  2. Signaling via Gt activates cGMP phosphodiesterase and lowers cGMP
  3. Signaling via Gq activates PLC and increases DAG, IP3, Ca2+
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25
Q

Same hormones can cause different responses in different cells

A
  1. Epinephrine in smooth muscle relaxes
  2. Epinephrine in cardiac muscle contracts
  3. B-adrenergic receptor in both ex
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26
Q

B-agonists and their effects

A
  1. B-agonist albuterol is a hydrophilic molecule that activates B2-adrenergic receptors
  2. Administered to lungs to treat airway-constricting conditions
  3. Pt’s unresponsive to albuterol given epinephrine to relax bronchiol smooth muscles and stimulate heart contraction (tachycardia)
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27
Q

Nitric Oxide (NO) and smooth muscle relaxation

A
  1. NO = endothelium-derived agent to relax smooth muscle.
  2. Generated from arginine, promoted by calmodulin (Ca2+)
  3. cGMP activates PKG –> smooth muscle relaxation and vasodilation
  4. NO is anti-anginal
  5. Pts taking nitroglycerin shouldn’t take meds that inhibit cGMP phosphodiesterase –> extreme drop in BP
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28
Q

Antihistamines inhibit GPCR signaling

A
  1. Symptoms of allergy caused by histamine (hydrophilic signaling molecule from histidine)
  2. Histamine binds to 4 histamine GPCRs (H1-H4)
  3. Antihistamines = lipophilic compounds that block binding of histamine to H1 GPCR to decrease allergic symptoms. Other antihistamines block H1 receptors and inhibit symptoms of motion sickness.
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29
Q

Epinephrine

A

B-adrenergic R –> Gs –> Relax SM, contract CM, breakdown glycogen in liver and muscle, glycolysis in muscle

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30
Q

Histamine

A

Histamine H2 R –> Gs –> bronchoconstriction and symptoms of allergies

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31
Q

Epinephrine/norepinephrine

A

A adrenergic R –> Gi –> SM constriction

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32
Q

Dopamine

A

dopamine D2 R –> increase HR

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33
Q

Acetylcholine

A

muscarinic acetylcholine M3 R –> Gq –> bronchoconstriction

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34
Q

Light

A

rhodopsin –> Gt –> vision

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35
Q

Receptor Tyrosine Kinases (RTK)

A
  1. Extracellular signaling molecule-binding domain
  2. Single alpha-helical transmembrane domain
  3. Intracellular domain to process tyrosine K activity
36
Q

Growth factors can bind to RTK and activate it

A
  1. Ligand binds to RTK
  2. Conformational change to cause receptor to dimerize
  3. Phosphotyrosine residues recognize and bind by adaptor and docking proteins
  4. Activate downstream signals that are RAS-dept or indept.
  5. Phosphorylation of protein targets
  6. Changes in transcription, protein activity
37
Q

RAS-dependent vs. RAS-independent

A

RAS-dept: facilitated by members of MAPK

RAS-indept: facilitated by other kinases

38
Q

RTK Signal Termination

A
  1. By degrading signaling molecules via proteases
  2. Ligand-induced endocytosis of receptors + lysosomal degradation
  3. Accelerated RAS inactivation
  4. Dephosphorylation of target proteins by phosphoprotein phosphatase
39
Q

RTK has long term AND short term effects

A

Long term: Gene transcription

Short term: Change in protein activity already present in cell

40
Q

Monomeric G-proteins

A
  1. RAS, possess GTPase activity
  2. Inactive when bound to GDP, active when bound to GTP
  3. RAS cycles b/w inactive and active states with GEF and GAP
41
Q

Insulin Signaling

A
  1. Insulin binds to RTK to regulate glycogen and TAG metabolism
42
Q

RAS dependent insulin signaling

A
  1. Insulin binds to RTK
  2. Autophosphorylation of receptor tyrosines
  3. P-tyrosines recognize and bound by insulin R substrate (IRS1)
  4. IRS1 gets phosphorylated on its tyrosine residues by insulin receptor
  5. P-IRS1 recognized and bound by GRB-2
  6. Activate RAS and MAPK cascade
  7. Phosphorylation of nuclear proteins, transcription of glucokinase
43
Q

RAS independent insulin signaling

A
  1. Insulin binds to RTK
  2. Autophosphorylation of receptor tyrosines
  3. P-tyrosines recognized and bound by IRS1
  4. IRS1 gets phosphorylated on its tyrosine residues by insulin receptor
  5. P-IRS1 recruits P13-kinase
  6. PI3-K phosphorlyates phosphoinositides to make PIP3
  7. PIP3 acts as second messenger to recruit PKB to membrane and phosphorylate it to make it active
  8. Active PKB (AKT) phosphorylates intracellular proteins
44
Q

Glycogen synthesis promoted by _______

A

Activated glycogen synthase

45
Q

RAS and Cancer

A
  1. Mutated RAS, GEF and GAP implicated in human cancer
  2. Mutations decrease intrinsic GTPase activity of RAS = locked in active state
  3. Neurofibromatosis (nerve tissue tumor) caused by inactivating mutation in NF-1 gene that codes for GAP and RAS in nerves, uncontrollable nerve tissue growth.
46
Q

Recognition Domains

A
  1. Adaptor proteins (GRB2, IRS1) have SH2 domains or PTB domains that can recognize and bind to phosphorylated tyrosine residues on the receptor.
47
Q

Small G-proteins

A
  1. 150+ members of RAS family of G-proteins play role in transduction of signals from membrane receptors to effector proteins
  2. Monomeric with 1 pp chain
  3. Control cell proliferation, vesicular trafficking, survival, apoptosis, cell shape, polarity, membrane transport, secretion
  4. RAS, RAB, RHO, ARF, RAN
48
Q

Insulin Resistance

A
  1. Loss of insulin stimulation of glucose uptake by GLUT4 in adipose and skeletal muscle
  2. Reduced activation of PKB by insulin in obese people
  3. Tyrosine phosphorylation of IRS1/2 is necessary to recruit PI3 kinase
  4. Serine/threonine inactivates IRS and degrades
  5. Serine/threonine phosphorylation of IRS1/2 stimulated by cytokines, FAs, and hyperinsulinemia
49
Q

Signal transduction

A

Cascade of events that requires signals, receptors and effectors

50
Q

Fast/Slow responses of cell signaling

A

Fast: Change in activity or function of ENZYMES or proteins in the cell, metabolic changes, fight/flight
Slow: Change in amounts of proteins by change in expression of genes

51
Q

Effects of defective cell signaling

A
  1. Leptin gene knockout mice
  2. Cancer
  3. ENDLESS POSSIBILITIES
52
Q

What is cell signaling?

A

Getting messages from the outside to the inside of the cell.

53
Q

2 types of signal responses

A

Fast (proteins, enzymes)

Slow (gene expression)

54
Q

3 main components of cell signaling

A

Signals, receptors, effectors

55
Q

2 types of signal receptors

A
  1. Intracellular receptors

2. Cell surface receptors

56
Q

Hydrophobic vs. Hydrophilic Receptors

A
  1. Hydrophobic molecules diffuse through membrane and bind to intracellular receptors.
  2. Hydrophilic molecules can’t diffuse and bind to cell-surface receptors (extracellular)
57
Q

Example hydrophobic ligands and signals

A

Cortisol, estradiol, testosterone, thyroxine, vitamin D3, retinoic acid

58
Q

Intracellular receptors are inactive by being bound to proteins –>

A

Ligands go to binding site, making conformational change in the receptor and allowing it to translocate to the nucleus.

59
Q

3 main types of cell signaling receptors in PM

A
  1. Ion channel coupled receptors (ligand gated)
  2. GPCR
  3. Enzyme coupled receptors (RTK)
60
Q

How many subunits to a G-protein?

A

Alpha, beta, gamma

Alpha associates with effector enzyme
Beta/gamma release to allow alpha to perform, are docking proteins

Alpha subunit itself is not an enzyme

61
Q

Do G-proteins have intrinsic catalytic activity?

A

No. G-proteins act on enzymes which perform the catalytic activity.

62
Q

GEF vs GAP

A

GEF: GDP –> GTP (not phosphorylation)
GAP: GTP –> GDP, (accelerates intrinsic GTPase activity)

63
Q

Adenylyl Cyclase

A

Effector molecule of GPCR (Gs), catalyzes formation of cAMP –> PKA

64
Q

cAMP

A
  1. Not recognized by kinases
  2. Activates cAMP dependent PKA (tetramer 2/2)
  3. Bind 2 cAMP molecules to regulator subunits and release active C subunits
  4. Active PKA can phosphorylate other proteins
65
Q

Signaling Amplification in cAMP Pathway

A
  1. ONE activated receptor protein can activate MANY adenylyl cyclases through G-protein (Gs)
  2. cAMP activates PKA –> enzymes
  3. Amplification at each step of secondary messenger
66
Q

Cholera Epidemic

A
  1. Modifies G-protein by keeping Ga in GTP active form indefinitely (prevents hydrolyzation of GTP)
  2. Leads to 100 fold increase in cAMP
  3. PKA phosphorylates CFTR Cl- channel
  4. Secretion of water
67
Q

Desensitization of Signal

A
  1. Turning off the signal
  2. Decrease hormone levels
  3. Remove signaling molecule (remove ligand)
  4. Receptor sequestration by endosomes
  5. Receptor destruction by endosomes + lysosomes (proteases)
68
Q

Phosphodiesterases will remove cAMP

A

Idea is to remove the signaling molecule

69
Q

G-protein receptor kinases (GRK) (GPCR-K)

A
  1. GRK phosphorylates the receptor
  2. Protein named ARRESTIN binds to protein
  3. Ga can’t interact, GDP can’t convert to GTP
70
Q

Gi/Go alpha G-proteins

A
  1. Inhibit adenylyl cyclase

2. No cAMP production, no PKA activation

71
Q

Gq alpha G-proteins

A
  1. Activates phospholipase C (PLC) instead of adenylyl cyclase (AC)
72
Q

Phospholipase C activation (PLC)

A
  1. PLC cleaves PIP2
  2. PIP2 –> IP3 and DAG (2nd messengers)
  3. IP3 –> triggers Ca2+ release from endoplasmic reticulum
  4. DAG activates PKC (major regulatory unit)
73
Q

Protein Kinase C (PKC)

A
  1. DAG induces conformational change in PKC and activates it

2. PKC phosphorylates membrane/cytoplasmic substrates.

74
Q

Enzyme-coupled receptors (3)

A
  1. Tyrosine Kinase receptors (RTK)
  2. JAK-STAT receptors
  3. Serine-threonine kinase receptors

All create docking sites for other proteins.

75
Q

Tyrosine Kinase Receptors (RTK)

A
  1. Single pass transmembrane domain
  2. Enzymatic domain is on cytoplasmic tail
  3. Induces dimerization of two receptor monomers
  4. Autophosphorylation occurs
76
Q

RTK Characteristics

A
  1. RTK used to respond to growth factors
  2. Growth factors are proteins released to promote growth of other cells

Growth factors are found in multiple cell types, not limited to where name states.

77
Q

Growth factor = RTK, no GPCR relation

A

Growth factor = anything–GF

78
Q

RTK Receptor Information

A
  1. Activated receptor binds to proteins with SH2 domains
  2. SH2 domain = Src homology
  3. Src = first oncogene discovered
  4. SH2 protein in mammals is Grb2 (adaptor protein)
79
Q

RTK Receptor Mechanism

A

RTK –> SH2 (GRB2) –> SH3 (GRB2) –> SOS (GEF) –> RAS (ATP Bound) –> RAF

80
Q

RAS is the most common oncogene

A

25% of cancers are RAS mutations

81
Q

RAF mechanism

A
  1. RAF/RAS complex initiates MAP kinase pathway
  2. MAP Kinase-Kinase-Kinase reduces to MAP Kinase (ERK)
  3. ERK regulates protein activity and changes in gene expression
  4. Phosphorylation propagates the signal downstream
82
Q

Insulin signaling

A
  1. RAS independent (PI3K) and RAS dependent (GRB2)
  2. RAS independent is fast, RAS dependent is slow
  3. Receptor binds to IRS-1 intermediate –> GRB2 for slow pathway, PI3K for fast pathway
83
Q

RTK effective pathway

A

RTK leads to gene transcription through MAP kinase pathway

84
Q

Proto-oncogenes

A

Proto-oncogenes mutate into oncogenes and cause cancer.

85
Q

JAK-STAT Receptors

A
  1. More direct route for impacting gene transcription
  2. Receptors bind cytokines, dimerize and bind JAKs
  3. JAKs cross phosphorylate each other and receptor
  4. Receptor binds and phosphorylates STATs
  5. STATs dissociate from receptor, dimerize and translocate to nucleus
86
Q

Serine-threonine receptors & Smad

A
  1. More direct route
  2. Activated receptor (dimer) phosphorylates R-Smad
  3. R-Smad complexes with Co-Smad and migrates to nucleus
  4. Smads can control cell proliferation AND differentiation
87
Q

Src vs. RAS

A
  1. Src was the first oncogene to be discovered

2. RAS mutations are found in 25% of cancers

Molecular & Cellular Mechanisms (11 decks)

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