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Pharm Block 1 > 7 - Signal Transduction > Flashcards

7 - Signal Transduction Flashcards

1
Q

Why is signal transduction important?

A

In a multicellular orgniams, cells need to respond to signals in order to communicate with each other.

It’s essential for normal function.

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2
Q

What must happen for a signal to induce a cellular response? What allows this to occur?

A

It needs to get across the PM, be transduced through the cytoplasm into the nucleus, and then specific genes need to be expressed.

Receptors and intracellular signaling molecules allow these events to occur.

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3
Q

What is the first type of cell signaling?

A

Signaling by secreted molecules:

  • Local mediators are secreted by the signaling cell and received by surrounding targets.
  • Mediators are secreted and received by the same cell
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4
Q

What are two methods by which signaling occurs through secreted molecules?

A

Synaptic signaling: Nts are secreted by pre-synaptic nerve cell into synaptic cleft and are received by the post-synaptic cell.

Endocrine signaling: hormones secreted into bloodstream which carries hormones to distant target cells.

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5
Q

Other than signaling by secreted molecules, what is a second type of cell signaling? What does this require?

A

Signaling by plasma-membrane bound molecules.

The signaling molecule is a transmembrane protein, in which the extracellular domain acts as a ligand for the receptor on the target cell.

This requires that the target cell is in direct contact with the signaling cell.

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6
Q

What do intracellular steroid receptors bind? What are their two unique characteristics?

A

Bind small, hydrophobic signaling molecules such as steroid hormones, thyroid hormones, retinoids, and VitD.

Characteristics:

  1. Receptors are intracellular, interact with ligand in cytoplasm or nucleus
  2. These receptors are ligand-activated transcription factors
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7
Q

What is the structure of steroid receptors? What happens when the receptor binds?

A

Have hormone binding site, DNA-binding domain, and a transcription activation domain.

Receptor binding steroid hormone causes it to dissociate from inhibitory proteins, allowing DNA binding domain to interact with DNA.

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8
Q

What is an example of an intracellular steroid receptor? How do steroid hormones get to the target cell?

A

Glucocorticoid receptor (GR) activated by cortisol (S).

Steroid hormones travel in blood boudn to carrier proteins and dissociate before entering the target cell - called corticosteroid-binding globulin (CBG).

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9
Q

The glucocorticoid receptor (GR) is an ______ complex in the cytosol, associated with ______ and other cytosolic proteins.

A

Inactive

HSP90

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10
Q

What happens once cortisol (S) is released from the coricosteroid-binding globulin (CBG) what happens?

A

Cortisol passively diffuses through the PM and binds to the receptor (GR), causing the GR to dissociate from the inhibitory proteins.

Released GR (still bound to cortisol) then translocates to the nucleus.

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11
Q

What happens once the active GR, attached to cortisol, gets into the nucleus?

A

It dimerizes and binds with high affinity to a conserved DNA sequence known as the glucocorticoid-response element (GRE).

GRE is a hormone-response element that causes either an increase or decrease in transcription of the target gene when bound.

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12
Q

Glucocorticoids are useful _________ agents due to their gene regulation?

A

Anti-inflammatory.

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13
Q

What are three types of membrane receptors?

A
  1. Ion channel-linked receptors
  2. Protein-coupled receptors
  3. Enzyme-linked receptors
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14
Q

What are the characteristics of ion channel linked receptors (aka ligand-gated ion channels or ionotrophic receptors)?

A

Receptors for Ach, GABA, serotonin, and glycine have 5 subunits. For glutamate has 4 subunits.

Receptor directly controls the opening and closing of the ion channel.

Activation lads to very rapid changes in ion flux, resulting in rapid signaling.

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15
Q

What is an example of an ion channel linked receptor? What are the subunits? What does it bind?

A

Nicotinic Acetylcholine receptor:

  • Consists of 5 subunits: alpha 1 and alpha 2, beta, delta, gamma
  • Binds acetylcholine to the alpha subunits and opens channel, causing influx of cations.
  • Results in depolarization and excitation (this is why Ach is excitatory).
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16
Q

Where are nicotinic Ach receptors located?

A

In the neuromuscular junction (NMJ), the peripheral autonomic nervous system (PNS), and the CNS.

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17
Q

What type of signaling occurs with GABA receptor-gated Cl- channels? What is GABA? What is the result of this?

A

Gamma-aminobutyric acid: a primary post-synaptic inhibitory nt in the CNS.

GABA binds receptor > Cl- channel opens > influx of Cl into cell >hyperpolarization and inhibitory response.

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18
Q

What type of medications bind to GABA receptors?

A

Barbituates and benzodiazepines binds and potentiate the inhibitory action of GABA by allowing lower ceoncentration of GABA to open the channel to cause hyperpolarization.

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19
Q

What is a G-protein coupled receptor?

A

A single protein that passed through the PM seven times.

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20
Q

What is a G-protein coupled receptor almost always associated with? What is the function of this?

A

A heterotrimeric G-protein transducer made of an alpha, beta, and gamma subunit that functions to link the GPCR to the effector enzymes.

Heterotrimeric g protein cycles between two states: GDP bound (inactive) and GTP bound (active).

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21
Q

What are the functions of the GPCR receptor system?

A
  1. Receptor provides specificity
  2. Heterotrimeric G protein is the transducer
  3. Effector provides catalytic component to generate the 2nd messenger
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22
Q

Describe the three subunits of heterotrimeric G proteins?

A

Galpha: binds GTP and is released from Gbetagamma to interact with effectors. Hydrolyzes GTP to GDP (GTPase activity) and rebinds with betagamma.

Gbetagamma: inhibits Galpha and anchors to membrane. Has its own effectors.

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23
Q

What are the different Galpha subunits of heterotrimeric G proteins? What is each of their functions?

A

GalphaS: stimulates adenylyl cyclase

Galphai: inhibits adenylyl cyclase

Galphaq: activates phospholipase C

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24
Q

What are the four types of enzyme-linked receptors?

A
  1. Tyrosine kinase-linked receptors
  2. Serine/threonine kinase-linked receptors
  3. Protein phosphatase-linked receptors.
  4. Guanylyl cyclase-linked receptors
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25
Q

What is the structure and action of tyrosine kinase-linked receptors? What are the two ways this can occur?

A

Each receptors is a single protein with one transmembrane domain which dimerizes upon binding of ligand.

OR

Each receptor is composed of two subunits which form a tetramer upon binding of ligand.

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26
Q

An insulin receptor is a tyrosine-kinase linked receptor. What is it’s structure when its active and inactive?

A

Alpha and beta associate via disulfide bonds.

When ligand is present, two inactive dimers come together to form an active tetramer.

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27
Q

Why are tyrosine kinase-linked receptors named the way they are? What are two examples besides the insulin receptor?

A

Because each of the receptors has a cytoplasmic domain that has tyrosine kinase activity.

These can also bind cytoplasmic proteins that are also tyrosine kinases or other enzymatic activities.

EGF and PDGF receptor.

28
Q

What does ligand binding cause the tyrosine kinase linked receptor to do?

A

Dimerization and activation by cross-autophosphorylation.

Binding of intracellular signaling molecules.

29
Q

What is the importance of tyrosine kinase linked receptors?

A

Regulators of cell proliferation and differentiation in response to hormones like insulin, growth factors such as epidermal growth factor (EDG) platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VAGF).

Play a role in oncogenesis and are targets for some chemo drugs.

30
Q

What is the first component of intracellular signaling pathways? What else must be present to transduce and process a signal?

A

Receptors! Can be intracell or membrane bound.

Intracellular signaling molecules must typically be present to transduce and process a signal through the cytoplasm and into the nucleus.

31
Q

What are four types of intracellular signaling molecules?

A

G proteins (heterotrimeric or monomeric)

Second messengers (not proteins)

Protein kinases and phosphatases

TFs

32
Q

What are transcription factors? What is a ubiquitous TF that activates many genes? What are some others?

A

Proteins that bind DNA and regulate (promote or inhibit) transcription of genes.

CREB (cAMP response element binding protein)

Others: Myc, Fos, Jun

33
Q

What are some important properties of TFs?

A

Nuclear translocation and ability to bind DNA.

Activate RNA polymerase, resulting in transcription of mRNA from target gene.

34
Q

What is the action of protein kinases? What are the three groups?

A

Catalyze addition of phosphate group to side chain of aas (serine, threonine, tyrosine) in proteins and peptides.

  1. Serine/threonine specific protein kinases
  2. Tyrosine-specific protein kinases
  3. Dual specificity kinases: that can phosphorylate both threonin and tyrosine MAPKK1
35
Q

The activities of protein kinases and protein phosphatases are regulated by _________.

A

second messengers.

36
Q

What are second messengers? What is an example?

A

Small diffusible molecules (NOT proteins) that are generated in response to ligand-receptor interactions and activate downstream effectors.

Cyclic adenosine monophosphate (cAMP)

37
Q

How is cAMP made? How does it act as an effector?

A

cAMP made when GalphaS activates adenylyl cyclase. Activated adenylyl cylase converts ATP to cAMP.

cAMP activates protein kinase A (PKA).

38
Q

Other than cAMP, what are two other second messengers?

A

Diacylglycerol (DAG) and inositol triphosphate (IP3).

39
Q

How are DAG and IP3 made? What are their effector functions?

A

When Galphaq activates phospholipase C (PLC). Activated PLC cleaves PIP2 to generate DAG and IP3.

DAG activates protein kinase C (PKC) and IP3 binds to IP3 receptors of the ER, releasing calcium from the ER.

40
Q

Besides cAMP, DAG, and IP3, what is another important 2nd messenger? How is it generated and what are its effects?

A

Ca2+: generated by opening of ion channels.

Binds to proteins and activates Protein kinase C (PKC) and other kinases and enzymes.

41
Q

What is the cAMP pathway?

A
  1. Binding of ligand to the GPCR activates GalphaS
  2. Active GalphaS-GTP binds adenylyl cyclase and activates it.
  3. Each activated adenylyl cyclase generates many cAMP from ATP.
  4. cAMP molecules activate protein kinase A (PKA).
42
Q

How do cAMP molecules activate PKA?

A

cAMP binds to the regulatory subunits of PKA, causing the catalytic subunits to dissociate and those catalytic subunits can then go to phosphorylate their substrates.

43
Q

What happens in the pathway when caMP molecules activate PKA?

A

Each PKA can phosphorylate and activate many copies of CREB (cAMP response element binding protein)

Activated CREB binds to DNA and induces gene transcription.

44
Q

Does PKA only have one substrate?

A

NO.

It can phosphorylate many different substrates, which can produce many responses.

45
Q

What are the steps of the inositol-lipid pathway?

A
  1. Ligan activates GPCR coupled to Galphaq.
  2. Galphaq activated by binding GTP and dissociates from BY.
  3. Galphaq-GTP binds and activates phospholipase C (PLC)
  4. PLC cleaves PIP2 into IP3 and DAG
  5. DAG remains in membrane and activates PKC.
  6. IP3 diffuses into cytoplasm and causes Ca2+ release from ER.
  7. Ca binds calmodulin and activates Ca/calmodulin dependent kinases.
46
Q

What is the function of GalphaA? Galphai? Galphaq?

A

GalphaA: increase cAMP
Galphai: decrease cAMP
Galphaq: increase IP3, DAG, and Ca2+

47
Q

What are some monomeric G proteins? How are they activated and inactivated?

A

Ras, Rho, Rac, Rap, Rab.

Activated by interacting with proteins known as guanine nucleotide exchange factors (GEFs).

Inactivated by interacting with proteins called GTPase activated proteins (GAPs)

48
Q

Whats the difference between heterotrimer and monomeric g proteins?

A

Heterotrimeric (Galpha) are activated by direct interaction with GPCR.

Monomeric (such as Ras): activated by direct interaction with a GEF.

49
Q

What is the function of guanine nucleotide exchange factors (GEFs)? What is an example of one?

A

SOS

Activated when they are recruited to activated tyrosine kinase linked receptors by adaptor proteins such as GRB2.

50
Q

How does Ras get activated? What happens next?

A

When it interacts with GEF (such as SOS) Ras-GDP releases GDP and binds GTP to form active complex.

Active Ras-GTP bind sand signals other molecules and have intrinsic GTPase activity.

51
Q

What happens when Ras-GTP associates with a protein called GAP (GTPase-activating protein)?

A

The GAP induces Ras-GTP to hydrolyze GTP to GDP, resulting in an INACTIVE Ras-GDP.

Ras-GDP is inactive until a new signal causes it to associate with a GEF.

52
Q

What is the Mitogen-activated protein (MAP) kinase signaling cascade?

A
  1. Activated monomeric G protein activates MAP kinase kinase kinase
  2. Phosphorylation and activation of MAP kinase kinase
  3. Phosphorylation and activation of MAP kinase
  4. Phosphorylation of Transcription Factor (the MAP in this case)
53
Q

What does activated Ras (Ras-GTP) do? Be specific.

A

Activates Raf, a MAP kinase kinase kinase.

Raf phosphorylates MKK!, MKK! is a MAP kinase kinase

MKK1 phosphorylates ERK, ERK is a MAP kinase.

ERK phosphorylates many TFs.

54
Q

What are the steps that occur before Ras-GTP activate the MAP kinase pathway (ie how does Ras get activated)?

A

Ligand binds the receptor and causes dimerization and cross-phosphorylation of the receptor.

Phos. receptor binds adaptor GRB 2, which binds GEF called SOS.

SOS activates Ras by causing it to release GDP to bind GTP.

Ras-GTP activates MAP kianse pathway.

55
Q

What do mutations in the EGF receptor of Ras result in?

A

Mutations cause abnormally high activity of this pathway and may promote tumorgenesis and metastasis.

56
Q

What are getfitinib and erlotinib? What enhances the efficacy of these drugs?

A

Tyrosine kinase inhibitors that target the kinase domain of the EGF receptor and inhibit signaling by the EGF receptor.

Efficacy enhanced by presence of mutations in the EGF receptors expressed by the tumor.

Without the mutation in the EGF receptor, pts are not as good ofg candidates for these drugs.

57
Q

When does adaption of a signal occur? What is an example of adaptation that occurs?

A

When the signaling system responds to the intensity and frequency of stimulation and the response is proportionate to the stimulus.

Receptor-mediated endocytosis regulates the number of receptors tat can respond to a signal an d can promote degradation of the receptor and the ligand.

58
Q

What induces receptor mediated endocytosis? What occurs in the absence of this?

A

Induced by binding of the ligand to the receptor causes receptors on the PM to migrate to coated pits and undergo endocytosis.

In absence of ligend, receptors might not be localized in the specific location of the PM.

59
Q

What transient structure forms during receptor mediated endocytosis?

A

Coated pits are specialized inward curves membranes where receptor-mediated endocytosis occurs

They are electron dense cages formed by the structural protein clathrin.

60
Q

How do clathrin coated pits endocytose signals? What is the pH of the vesicles?

A

They pinch off as a vesicle and fuse with tubular-reticular structures called CURL (compartment of uncoupling of receptor and ligand).

These vesicles have a low pH (4.5-5) and favor dissociation of the ligand.

61
Q

What happens to the ligands endocytosed by clathrin coated pits? What happens to the free receptor in CURL?

A

Most ligands incorporate into vesicles which fuse with lysosomes, but some are recycling in retroendocytosis.

Free receptor in CURL may recycle to the cell membrane or be sequestered and down-regulated.

62
Q

What occurs in homologous desensitization? When can this occur?

A

Signaling by the stimulated receptor (ONLY) is attenuated.

This can occur due to covalent modification (phosphoarylation) of the ligand-bound receptor.

63
Q

Give and example of how homologous desensitization of a GPCR occurs?

A

Upon phosphorylation of the receptor by B-adrenergic kinase (BARK) and subsequent binding of B-arrestin to the phosphorylated receptor.

64
Q

What other molecule can cause homologous desensitization of a GPCR?

A

Phosphorylation of the receptor by PKA.

65
Q

What is heterologous desensitization? When can this occur?

A

Signaling by BOTh the stimulated receptor and by other different receptor types is attenuated. BOTH stimulated and unstimulated receptors are blocked.

Can occur due to covalent modification (phosphorylation) of the receptors or by other things like 2nd messengers.

Pharm Block 1 (11 decks)

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