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BIOCHEM 2 > Chapter 10 Fundamentals of Biosignaling > Flashcards

Chapter 10 Fundamentals of Biosignaling Flashcards

1
Q

What is cell signaling?

A

Cell signaling is the process by which cells communicate with one another to coordinate their activities and respond to environmental changes.

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2
Q

Why is cell signaling necessary?

A

Necessary to maintain a normal, healthy physiology.

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3
Q

What was Sequard’s Experiment?

A

Sequard injected himself every morning with fresh extracts of ground dog testicles. This first introduced the idea that a particular molecule could affect the signaling pathway of a cell.

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4
Q

What did Banting and Best do?

A

Protein extract prepared from dog pancreas could lower blood glucose levels. Molecule discovered was insulin.

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5
Q

What are the challenges for studying signaling?

A

Low abundance of molecules in cell.
Signaling is a time-dependent process.
State of a cell signaling system varies with cell type.
Cell signaling involves highly interconnected systems.

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6
Q

What are the classes of hormones (first hormones)?

A

Endocrine: released in blood and carried throughout the body.
Paracrine: released into intracellular space, diffuses to neighboring cells.
Autocrine: affect the cells that release them.

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7
Q

What are agonists?

A

Activators of the cell response.

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8
Q

What are antagonists?

A

Molecules that block the response of agonists.

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9
Q

What are inverse agonists?

A

Blocks agonist and can turn off basal response.

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10
Q

What are the two independent metrics for evaluating the efficacy of an agonist on a receptor?

A

Bmax: total response of agonist
EC50: concentration required to reach 50% of the maximal effect.

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11
Q

What are the major classes of cell signaling systems?

A

Ionotropic: receptor is a ligand gated ion channel. Ex: nicotinic acetylcholine receptor.

Metabotropic: receptor is an allosterically regulated non-classical enzyme. Ex: G-protein coupled receptor.

Enzyme-Linked Receptor: receptor is a classical enzyme.

Nuclear: receptor is an allosterically regulated transcription factor. Ex: steroid receptors.

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12
Q

Ligand Gated Ion Channel

A

Modulates activity of intracellular proteins and changes cell electrical potential.
Acetylcholine is a family of ligand gated ion channels. Speed is important for this channel, immediately after the binding of the ligand, ions begin to flow through the channel.
Acetylcholine receptor binds to the extracellular portion of the protein which causes a rotation of the transmembrane domains allowing the passage of ions.

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13
Q

What is an agonist of the acetylcholine ion channel?

A

Nicotine agonist (activator) of channel, chantix weak agonist of the receptor.

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14
Q

Many agonists activate more than one type of receptor, for example acetylcholine activates two distinct classes of receptor. How can we distinguish?

A

Distinguished by ability to be activated by other types of receptors.
Ionotropic acetylcholine receptor: activated by nicotine.
Non-ionotropic acetylcholine receptor: activated by muscarine.

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15
Q

What are mechanosensitive channels?

A

Involved in physiological functions including osmotic regulation, touch, and hearing. Ions channels that open in response to mechanical tension on the cell.

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16
Q

What are transient receptor potential channels?

A

Found in neurons for detecting sensation. Na+ and Ca2+ permeant channels gated by temperature.

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17
Q

What is the TRPM8 channel?

A

Channel that produces the sensation for cold.

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18
Q

How does the TRPM8 channel open?

A

Low temperature, results in conformational change that gates the channel open.

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19
Q

What are agonists of the TRPM8 channel?

A

Menthol, icilin

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20
Q

What is the TRPV1 channel?

A

Channel for detecting heat.

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21
Q

How does the TRPV1 channel open?

A

High temperature results in conformational change that gates the channel open.

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22
Q

What are agonists for the TRPV1 channel?

A

Capsaicin.

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23
Q

Why do cells use enzymes as the foundation for metabotropic signaling pathways?

A

Amplification: enzymes can amplify signals generated by the receptor leading to a large amplification of the signal.

Timing (through G-proteins): G-proteins are enzymes that cleave GTP —> GDP. Once GTP is cleaved to GDP, protein inactive, signaling mechanism terminates.

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24
Q

How and why does the timing in cell signaling differ for the timing mechanism used in periodic clocks such as the cell cycle or the circadian clock?

A

For cell signaling we want a discrete stop and end, therefore, G-proteins are used because they behave as stopwatches. CDK behaves like a clock and wants to do its own job, and catalyzes its own destruction.

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25
Q

What is the general mechanism for timing in cell signaling?

A

GTP hydrolyzing activity acts as a timer, once GTP has been hydrolyzed to GDP, the protein is off until activated by GEF.

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26
Q

What are second messengers?

A

Small ions or molecules that are either released into the cytoplasm or synthesized in the cytoplasm in response to activation of a signaling receptor.

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27
Q

What are three simple steps needed to produce second messengers?

A

Receptor binds to the agonist.
Activation of intracellular enzymes.
Second messengers produced.

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28
Q

Mechanism for biosynthesis of two second messengers cAMP and cGMP

A
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29
Q

Products for the structure of the molecules produced with cAMP and cGMP are the substrates for cyclic nucleotide phosphodiesterases.

A
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30
Q

What is the mechanism of activation for G-protein coupled receptors?

A

G-alpha is bound to G-beta gamma and is in the GDP bound state.

A ligand binds to the extracellular side of the GPCR.

Conformational change in GPCR allows it to interact with a G-protein.

Activated GPCR catalyzes exchange of GDP for GTP on the G-protein alpha subunit.

Alpha subunit dissociates from the beta-gamma complex.

G-alpha activated.

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31
Q

What is the G-alpha stimulatory?

A

Acts as an allosteric activator of the enzyme adenylate cyclase.

32
Q

Describe G-alpha stimulatory pathway.

A

The G-alpha (GTP) binds to and activates the membrane enzyme adenylate cyclase.

Adenylate cyclase catalyzes the reaction
ATP —-> cAMP + PPi.

cAMP can activate Protein Kinase A (PKA).

PKA enters the nucleus and phosphorylates a transcription factor protein CREB.

CREB activates the expression of some genes while repressing others.

33
Q

What motif does CREB use to bind to DNA?

A

Leucine zipper

34
Q

What is G-alpha inhibitory?

A

Acts as an allosteric inhibitor of the enzyme adenylate cyclase.

35
Q

Describe the pathway of G-alpha inhibitory.

A

G-alpha inhibitory binds to adenylyl cyclase and inhibits its activation and production of cAMP.

36
Q

What is G-alpha q ?

A

Acts as an allosteric activator of the enzyme Phospholipase C.

37
Q

Describe the G-alpha q pathway?

A

Binding of a ligand to a GPCR that activates Gq.

Gq binds to the enzyme phospholipase c and activates it.

Phospholipase C catalyzes the reaction PIP2 + H2O —-> DAG + IP3.

IP3 goes to ER and opens up calcium channels. DAG activates Protein Kinase C.

38
Q

What are important functions of the G-beta gamma?

A

Opening of the potassium channel, can also activate phospholipase C independently of protein kinase C.

39
Q

What is calmodulin?

A

Calcium binding protein that has EF hand motif, the ion that is bound is Ca2+.

40
Q

What is the protein regulated by calmodulin?

A

Calmodulin kinase (CAMKs).

41
Q

What is homologous desensitization vs. heterologous desensitization?

A

Homologous desensitization: pathway self silences, signaling pathway silences itself. Heterologous desensitization: another pathway silences the main pathway.

42
Q

Describe the pathway for homologous desensitization of GPCRs?

A

This pathway involves two additional proteins GRKs (G-receptor kinases and arrestins).

GRKs only phosphorylate activated GPCRs.

Arrestin proteins bind only to phosphorylated GPCRs, blocking heterotrimeric G-proteins from binding to the GPCR.

43
Q

What are the two consequences of arrestin binding to GPCRs?

A

Arrestin bound GPCR may associate with proteins called clathrins.

Clathrins in endosomes have two fates; 1. Secretory pathway and 2. GPCR may be degraded and destroyed.

44
Q

What is the function for which arrestins were originally named? Is this the only function of arrestin?

A

The function for which arrestins were originally named was for its ability to arrest signaling.

Another function of arrestin is it is capable of activating other signaling proteins, namely protein kinases.

45
Q

What is biased agonism?

A

When G-protein signaling or arrestin signaling is strongly favored over another.
Some compounds produce largely G-protein signaling while others produce largely arrestin signaling. Some physiological consequences only arise from arrestin signaling while others only arise from G-protein signaling.

46
Q

What are tyrosine kinases?

A

Tyrosine kinases are proteins that add phosphate groups to tyrosine.

47
Q

What are the unique features of receptor tyrosine kinases?

A

The binding site for the agonist is extracellular while the enzyme active site is intracellular.

Autophosphorylation: kinase activity in each chain phosphorylates its partner (one chain serves as the substrate for the other chain)

48
Q

What are adaptor proteins? What is the function of adaptor proteins?

A

Adaptor proteins are proteins that function to bring together other proteins. Instead of each protein having a binding site, one adaptor protein has the binding site for all proteins.

49
Q

How are adaptor proteins utilized in the receptor tyrosine kinase pathway?

A

The adaptor protein GRB2 contains an SH2 domain that binds to phosphorylated tyrosine residues on activated RTKs.

SH3 binds to proline rich sequences on signaling protein SOS. This leads to activation of the signaling pathway.

50
Q

What is binding specificity of PH domains?

A

binding of proteins to lipids with inositol phosphate head groups such as PIP3.

51
Q

What is the binding specificity of SH2 domains?

A

bind to phosphorylated tyrosine residues.

52
Q

What is the binding specificity of SH3 domains?

A

bind to proline rich peptide sequences.

53
Q

How is the substrate for a PH domain generated?

A

PI3 kinase

54
Q

How is the substrate for a PH domain destroyed?

A

PTEN

55
Q

How does the balance of PTEN and PI3-Kinase activity regulate cell signaling?

A

PI3 kinase catalyzes the phosphorylation of the lipid PIP2 to PIP3.

PTEN carries out the reverse reaction of converting PIP3 back to PIP2.

56
Q

What are two different receptor tyrosine kinases?

A

Epidermal growth factor receptor (EGFR) and insulin receptor

57
Q

What is the EGFR pathway?

A

EGF is an agonist for a growth factor (tyrosine kinase) receptor.

  1. Binding of 2 EGF proteins to the exofacial side of the receptor.
  2. The previous step leads to transphosphorylation of the intracellular receptor tails.
  3. SH2 domain of GRB2 binds to the phosphorylated tails. 2 SH3 domains of GRB2 binds to a GEF protein SOS.
  4. SOS displaces a GDP from the G protein Ras and replaces it with a GTP activating it.
  5. MAP Kinase Pathway
58
Q

What are the steps in the MAP Kinase pathway for the EGFR pathway?

A
  1. Raf is a serine/threonine kinase that binds to Ras(GTP) but not Ras(GDP).
  2. Active Ras-GTP recruits Raf to membrane and activates it.
  3. Src is a membrane associated tyrosine kinase that is activated by Raf.
  4. Raf phosphorylated by Src.
  5. Raf phosphorylates MEK which phosphorylates ERK.
  6. Phosphorylated ERK enters into the nucleus where it regulates gene expression by phosphorylating transcription factors.
59
Q

What are the steps for the insulin receptor pathway?

A
  1. The insulin receptor binds to insulin
  2. initiates cross phosphorylation of intracellular domains.
  3. Insulin receptor substrate binds to the intracellular phosphorylated domain
  4. The insulin receptor substrate becomes phosphorylated and activates the enzyme PI3K.
  5. PI3K catalyzes reaction of PIP2 —> PIP3.

PIP3 lipids bind through PH domains to PDK-1 and Akt.

  1. PDK-1 phosphorylates Akt.
  2. Phosphorylated Akt leaves the membrane and phosphorylates other substrates such as glycogen synthase. GLUT4 transporter is also upregulated.
60
Q

EGFR Pathway vs. Insulin Receptor Pathway

A

IR is a dimer of dimers and is always in tetrameric form.

Insulin receptor only binds to a single molecule of insulin.

61
Q

What are gas transmitters?

A

Are small molecules with low or no polarity that can rapidly diffuse throughout the body and act on signaling receptors.

62
Q

What is the receptor for nitric oxide?

A

a member of the receptor guanylyl cyclases.

63
Q

What reaction do guanylyl cyclases catalyze?

A

Guanylyl cyclases catalyze the reaction GTP —> cGMP + PPi

64
Q

What are the two broad classes of receptor guanylyl cyclases?

A
  1. Transmembrane
  2. Soluble enzyme located in the cytoplasm.
65
Q

What are the steps in the nitric oxide signaling pathway?

A

The ligand is a gas (NO).

  1. Nitric oxide produced in endothelial cells enter into adjacent smooth muscle cells and activate the enzyme guanylate cyclase.
  2. Production of cGMP which activates Protein Kinase G.
  3. This induces relaxation of smooth muscle.
  4. Termination occurs when phosphodiesterase cleaves cGMP into GMP.
66
Q

What is the significance of viagra in the nitric oxide signaling pathway?

A

Inhibits phosphodiesterase which cleaves cGMP to GMP.

cGMP persists longer, prolonged vasodilation.

67
Q

Why is Viagra associated with the blue color?

A

Phosphodiesterase expressed in blue photoreceptor cells, inhibition causes a prolonged stimulation of blue photoreceptors.

68
Q

How are nuclear receptors different from the other receptors we have encountered?

A
  • Only function in the nucleus.
  • Do not work through second messengers.
  • Have no immediate signaling effects.
  • Have effects that persist much longer
69
Q

What is a common feature of agonists for SHR and metabolite receptors?

A

They are highly hydrophobic.

70
Q

What are the two general mechanisms by which the SHR/metabolite receptor function?

A
  1. starting in the cytoplasm
  2. starting in the nucleus
71
Q

Steps for starting in the cytoplasm for the SHR/metabolite receptor

A
  1. Hydrophobic steroid hormone crosses the membrane and enters the cytoplasm where it encounters an SR.
  2. Binding of SR causes dissociation of SR from HSP70 and dimerization of SR.
  3. Dimerization causes conformational change which results in nuclear localization signal.
  4. Hormone SR enters the nucleus which activates transcription of mRNA.
72
Q

What is the role of the chaperone HSP70?

A

we don’t want dimerization of SR until the ligand is bound.

73
Q

Steps for starting in the nucleus for the SHR/metabolite receptor

A

Starting in the nucleus
1. Hormone enters nucleus and binds to hormone receptor.

  1. Conformational change results in displacement of receptor protein.
  2. Receptor can act as activator protein, resulting in expression of genes.
74
Q

What are some important characteristics of the notch receptor?

A

Notch does not bind to soluble molecules.
The two cells must be spatially proximate.
Notch receptors are used exactly once.

75
Q

What is the pathway for the Notch signaling?

A

Notch receptor on one cell binds to the Notch ligand on an adjacent cell.

This binding induces proteolytic cleavage of the Notch receptor leading to the release of the intracellular domain of Notch which translocates to the nucleus and activates gene expression.

76
Q

Why does a soluble version of Notch ligand cause Notch signaling to not be observed?

A

The mechanical stretch of the Notch protein exposes a proteolytic cleavage site just proximal of the membrane allowing the cleavage to occur and freeing the NCID from the remainder of the protein.

BIOCHEM 2 (17 decks)

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