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Principles of Drug Action > Signaling Molecules > Flashcards

Signaling Molecules Flashcards

1
Q

What is Paracrine Signaling

A

Local mediators are secreted by the signaling cell and received by surround target cells

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2
Q

What is Autocrine Signaling

A

Mediators are secreted and received by the same cell

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3
Q

What is Synaptic Signaling

A

Neurotransmitters are secreted by the pre-synaptic nerve cell into the synaptic cleft and are received by the post-synaptic cell which can be another neuron or a muscle cell

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4
Q

What is Endocrine Signaling

A

Hormones are secreted into the blood stream, which carries hormones to distant target cells

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5
Q

What is Signaling by plasma membrane-bound molecules

A

The signaling molecule is a transmembrane protein, and its extracellular domain is a ligand for the receptor on the target cell. This requires that the 2 cells are in direct contact

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6
Q

What are the properties of Steroid receptors?

A
  1. Intracellular receptors
  2. Interact with the ligand in either the cytoplasm or nucleus
  3. These receptors are ligand-activated transcription factors (they will alter gene expression)
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7
Q

What are the properties of steroid receptors? What happens when a hormone binds?

A
  1. They have a hormone binding site
  2. A DNA-binding domain
  3. A transcription-activating domain

When the receptor binds a steroid hormone, the receptor dissociates from inhibitory proteins, allowing the DNA-binding domain to interact with DNA (alter transcription).

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8
Q

Tell me about the Gluccocorticoid Receptor.

A 
Gluccocorticoid receptor (GR) activated by Cortisol (S). Cortisol travels in the blood bound to Corticosteroid-Binding Globulin (because it is hydrophobic).
GR receptor is in the cytoplasm, Cortisol diffuses into the cell and binds to GR, which kicks off the Heat Shock & inhibitory proteins. 
The GR still bound to Cortisol then translocates to the nucleus and binds to the DNA.
The GR binds to its Response Element, in this case Gluccocorticoid-response element (GRE).

In general, gene regulation from steroid receptors can increase or decrease expression of target gene. Cortisol upregulates expression of about 6 of 1000 proteins in liver cells. Gluccocorticoids are useful anti-inflammatory agents due to their gene regulation.

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9
Q

Tell me about Ion Channel-Linked Receptors. (Also called Ligand-Gated Ion Channels or Ionotropic Receptors)

A

Composed of multiple related subunits. The receptor directly controls opening and closing of the ion channel. Activation leads to rapid exchange of ions resulting in rapid signaling.

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10
Q

Tell me about the Nicotinic Acetylcholine Recepor Structure and Function.

A

A 5 subunit ion channel that is Cation specific (Na+). Binding of ACh to the 2 alpha subunits opens the channel. Influx induces depolarization and excitation. ACh is an excitatory neurotransmitter.

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11
Q

Nicotinic Acetylcholine Receptor is found where?

A

Found at the Neuromuscular Junction, peripheral autonomic nervous system (PNS) and central nervous system (CNS).

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12
Q

Tell me about GABA Receptor Gated Cl- channels structure and effects.

A

Gamma-Aminobutyric Acid: Primary postsynaptic inhibitory transmitter in the CNS.
GABA binds receptor, Chloride channel opens, influx of Chloride into cell causes hyperpolarization and inhibitory response

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13
Q

Agonsists for GABA Receptor?

A

Barbituates and Benzodiazepine bind to GABA and potentiate (increase) the inhibitory action of GABA.
Allows less GABA to create response, or a greater response. It’s potentiated.

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14
Q

What about GPCRs

A

Common family. 7 transmembrane helices. A wide variety of ligands go to CPCRs is general. 2 types of GPCRs, there are the Heterotrimeric G proteins and the monomeric GTPases.

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15
Q

How does the Heterotrimeric GPCR function?

A

`1. Receptor provides specificity

  1. Heterotrimeric G Protein is the transducer
  2. Effector provides the catalytic component to generate the 2nd messenger
  3. It cycles between 2 states, the GDP-bound inactive state and the GTP-Bound active state.
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16
Q

What are the 3 main subunits of the heterotrimeric G proteins and what do they do? Subunits of the 1 GPCR.

A

G alpha: Binds GTP, interacts with effectors; hydrolyzes GTP to GDP (has GTPase activity)
G Beta, Gamma. Inhibits the G alpha when bound together; anchors to membrane, has its own effectors

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17
Q

What are the main 3 types of G alpha subunits of the heterotrimeric GPCR?

A

Different G alpha subunits:

  1. are activated by different receptors
  2. target different effectors

The three kinds are;
G alpha S (stimulates adenylyl cyclase)
G alpha i (inhibits adenylyl cyclase)
G alpha Q (activates phosholipase C)

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18
Q

What are Enzyme-linked Receptors?

A

They are a diverse group of receptors with intrinsic enzymatic activity. Some examples include;

  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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19
Q

Tell me about Tyrosine Kinase-Linked Receptors.

A

Each receptor is a single protein with 1 transmembrane domain, which dimerizes upon binding of ligand
or
each receptor is composed of 2 subunits which form a tetramer upon binding the ligand (like the insulin receptor)

Each of these receptors has a cytoplasmic domain that has tyrosine kinase activity but they can also bind cytoplasmic proteins that are also tryosine kinases, or have other enzymatic activities.

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20
Q

Functional structure of the Tyrosine Kinase-Linked Receptors. (ligand and then what)

A

Ligand binding causes the dimerization, then activation by cross-autophosphorylation, and then the binding of intracellular signaling molecules.

These receptors are important regulators of cell proliferation and differentiation is response to;

  1. hormones, such as insulin
  2. growth factors like epidermal growth factor (EGF)
  3. growth factor platelet-derived growth factor (PDGF)
  4. Vascular endothelial growth factor (VEGF)
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21
Q

What are the 4 classes of receptors? Targets for drug intervention.

A
  1. Intracellular Steroid Receptor
  2. Ion Channel-Linked Receptor
    3, G Protein-Coupled Receptor
  3. Enzyme-Linked Receptor (Tyrosine Kinase-Linked Receptor)
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22
Q

What types of Intracellular signals are used after the receptor?

A

G proteins
Second messengers
Protein kinases and protein phosphotases
transcription factors

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23
Q

Tell me about Transcription factors.

A

They are proteins that bind to DNA and regulate (promote or inhibit) the transcription of genes.

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24
Q

CREB? What is it? Who is it? Where does Creb live???

A

CREB is cAMP-Response Element Binding Protein.

It is a ubiquitous transcription factor that activates many different genes.

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25
Q

How do Transcription Factors interact with Signal Transduction Cascades?

A

Signal Transduction cascades regulate multiple properties of a transcription factor including its nuclear translocation and its ability to bind DNA.

26
Q

How do activated transcription factors induce transcription?

A

Bind to DNA and activate RNA polymerase, resulting in transcription of mRNA from the target gene

27
Q

How are many transcription factors activated and deactivated?

A

Via Kinases and Phosphatases.

28
Q

How/what Protein Kinases work/do?

A

Stick on a phosphate group to the side chain of serine/threonin/tyrosine in proteins and peptides

29
Q

Types of Protein Kinases (the 3 types)

A

Serine/Threonin-Specific protein kinases. PKA, PKC, Ca2+/Calmodulin-dependent kinase (CaM kinase), MAP kinase

Tyrosine-Specific Protein Kinases. Tyrosine Kinase-linked receptors (like epidermal growth factor receptor) and cytoplasmic kinases like Src and Abl

Dual specificity kinases, phosphorylate both threonine and tyrosine. MAP kinase kinases

30
Q

Protein Phosphatases

A

Cleave the phosphate group from the side chain (Serine/Threonine/Tyrosine)
in proteins and peptides

31
Q

How are proteins’ activity regulated?

A

The activity of a protein is often regulated by multiple kinases and phosphatases acting on them

32
Q

Activities of protein kinases and phosphatases are regulated by

A

second messengers

33
Q

What are second messengers?

A

Small, diffusable molecules generated in response to ligand-receptor interactions and activate downstream effectors

34
Q

Tell me about cAMP

A

Generated in response to G Alpha S subunit activating Andenylyl Cyclase. Activated Andenylyl cylcase converts ATP to cAMP.

cAMP activates protein kinase A (PKA)

35
Q

Tell me about DAG and IP3

A

DAG and IP3 are made when the G Alpha Q subunit activates phospholipase C.

The activated PLC cleaves Phosphatidylinositol 4,5 bisphosphate (PIP2) to generate DAG and IP3

Effect, DAG activates PKC
IP3 binds to IP3 receptors of the endoplasmic reticulum, releasing calcium from the endoplasmic reticulum.

36
Q

Tell me about Calcium as a second messenger.

A

Generated by opening the ion channels. i.e. ion channels of the ER opened by IP3 is response to PIP2 being split by PLC which was activated by GalphaQ

Effect, it binds to proteins and activates Protein Kinase C and other kinases and enzymes

37
Q

What is the cAMP pathway?

A

Binding of ligand to the DPCR activates G alpha S

Active G alpha S - GTP binds to adnylyl cyclase and activates it

Each activated adenylyl cyclase generates many cAMP molecules from ATP

cAMP molecules activate PKA

Each activated PKA can phosphorylate and activate many copies of substrate X

Each copy of Substrate X may activate many copies of the next downstream substrate

So the signal is greatly amplified

38
Q

How does cAMP activate PKA?

A

PKA has 2 regulatory units with cAMP binding pockets and 2 catalytic subunits. When cAMP binds it changes PKA conformation and allows the 2 regulatory compound to leave and do their thing (phosphorylate crap)

39
Q

How can G alpha S and G alpha i work at the same time in the same cell?

A

Cellular response is a conglomerate of all signals. So you could stimulate more cAMP by activating G alpha S and inhibiting G alpha i.
Or whatever.

40
Q

End result of G Alpha S, G Alpha i and G alpha q

A

G Alpha S, higher amounts and amplification of PKA and further signaling

G Alpha i, lower amounts of PKA activity

G alpha q, regulate the inositol-lipid pathway

41
Q

G alpha Q pathway. What is it !?!?!?!?!

A
  1. Ligand activates a GPCR that is coupled with G alpha Q
  2. G alpha Q is activated by binding GTP and dissociates from the beta and gamma subunits
  3. G alpha q - GTP complex binds and activates Phospholipase C (PLC)
  4. Active PLC hydrolyzes PIP2 to generate IP3 and DAG
  5. IP3 diffuses into the cytoplasm and releases Ca2+ from the ER
  6. DAG activates Protein Kinase C (PKC) at the membrane, which is enhanced by Ca2+
  7. Ca2+ can also bind to calmodulin which activates the CaM dependent kinase
42
Q

What are some monomeric G proteins

A

Ras, Rho, Rac, Rap, Rab etc

Also called Small GTP-binding proteins

Monomeric G proteins activated by interacting with proteins called GEFs and GAPs

43
Q

What are GEFs and GAPs

A

Monomeric G proteins are activated by proteins called “Guanine Nucleotide Exchange Factors” which swap the GDP (inactive) with a GTP (active G Protein)

They are deactivated by interacting with proteins know as GAPs or “GTPase activation proteins”

44
Q

What is the difference between Monomeric and Heterotrimeric G proteins?

A

Heterotrimeric G Proteins (like G alpha subunit) are activated by direct interaction with the GPCR. Monomeric G proteins (such as Ras) are activated by indirect interaction with a GEF

45
Q

Tell me about SOS (Son of Sevenless)

A

SOS is a GEF (Guanine Nucleotide Exchange Factor).

SOS (this GEF) is activated when they are recruited to an activated Tyrosine Kinase-Linked receptors by adaptor proteins

(The ligand binds to Tyrosine Kinase Receptor, which dimerizes and cross phosphorylates itself. An adapter is recruited which connects SOS to the Tyrosine Kinase Receptors. Ras is connected to the SOS GEF, so it can now swap the GDP to GTP in Ras and activate Ras.)

46
Q

Activation Cycle of Ras and Other Monomeric G Proteins

A

Ras interacts with a GEF (like SOS), the GEF causes the Ras-GDP to swap its GDP for GTP and is the active form (Ras-GTP).

Active Ras-GTP binds and signal to other molecules

Ras has instrinsic GTPase activity, which means Ras-GTP can hydrolyze the GTP into GDP

When Ras-GTP associates with a GAP (GTPase-Activating Protein), the GAP induces Ras-GTP to turn to Ras-GDP which inactivates it.

Ras-GDP is inactive until a new signal calls it to associate with another GEF (like SOS again).

47
Q

GEF

A

The guanine nucleotide exchange factor causes Ras to release GDP and bind GTP which activates Ras

48
Q

GAP

A

The GTPase-Activating Protein induces Ras to hydrolyze the bound GTP to GDP which inactivates Ras

49
Q

Monomeric G Proteins are important in the MAP kinase Signaling Cascade

A

MAP stands for Mitogen-Activated Protein

Activated Monomeric G Protein

Activates MAP Kinase Kinase Kinase

Phosphorylation and Activation of MAP Kinase Kinase

Phosphorylation and Activation of MAP Kinase

Phosphorylation of Transcription Factor The MAP or the Mitogen-Activated Protein in this case

Abbreviated

Monomeric G Protein
Activates MAP3K
Activates MAP2K
Activates MAP K
Phosphorylates Transcription Factor (MAP)
50
Q

What does Ras-GTP do (now that it is activated)

A

Ras-GTP activates Raf (Raf is the MAP 3K)

Raf Phosphorylates MKK1 (MKK1 is the MAP 2K)

MKK1 phosphorylates ERK (ERK is the MAP kinase)

ERK phosphorylates many different transcription factors (in this case promotes proliferation of cells and causes cancer when overdone)

51
Q

What does Ras do?

A

Activated Ras activates the MAP kinase signaling cascade.

The ligand binds the receptor and causes dimerization and cross autophosphorylation of the receptor (the receptor tyronsine kinase)

The phosphorylated receptor binds the adaptor (GRB2) which then beinds the GEF, SOS.

SOS activates the Ras by causing it to release GDP and bind GTP (in other words the function of a GEF is to kick off GDP and let it bind GTP)

Ras-GTP activates the MAP kinase pathway

Ras, to Raf, to MKK1 to ERK to phosphorylating transcription factors (cell proliferation).

52
Q

What happens with mutations in the EGF receptor?

A

Mutations in the EGF receptor or in Ras occur in several types of tumors. These mutations cause abnormally high activity of this pathway and may promote tumor genesis and metastasis.

53
Q

So if EGF is overactive, then what?

A

Overactive Epidermal Growth Factor is caused by its receptor tyrosine kinase (The EGF receptor) or its monomeric g protein (like Ras) being overactive. It causes excessive growth and tumors/cancers.

Agents that inhibit signaling by the EGF receptor can then be used as chemotherapeutics.

Gefitinib and Erlotinib are tyrosine kinase inhibitors that target the kinase domain of the EGF receptor and inhibit singaling by the EGF receptor.

54
Q

Erlotinib and Geditinib

A

Decrease tumor burden in overactive EGF Receptor pathway in 80% of patients

Patients with a very specific mutation in the EGF receptor, unfortunately not all overactive EGF Receptor cancer patients.

It helps Adenocarcinoma of Female patients of Asian descent who have never smoked (the most)

55
Q

What about Signal attenuation?

A

Cells need to turn signals off. Not being able to turn signals off contributes to cancer.

Turn off a signal by;

  1. Ligand inactivation or dissociation from the receptor
  2. Receptor dissociates from other protein (like the adapter or GEF in monomeric G protein path)
  3. G proteins hydrolyze to GDP (not GTP bound)
  4. change phosphorylation to inactive state (protein in path)
  5. Second messengers metabolized or diffuse away
  6. Ions are sequestered or pumped out
56
Q

Receptor-Mediated Endocytosis

A

Receptor Attenuation of Adaptation. Turning a signal down.

Receptor mediated endocytosis takes away the number of receptors that can respond to the signal so that there is less effect.

Upon ligand binding the receptors migrate to coated -pits and undergo endocytosis

57
Q

Coated Pits

A

Electron dense cages formed by clathrin. Collect ligand bound receptor and endocytose them to attentuate signal or recycle the receptor. Or turn off the signal.

58
Q

CURL?

A

CURL is the Compartment of Uncoupling of Receptor and Ligand.
Clathrin-coated pits endocytose and take ligan bound receptors with them. Combine with CURL which have low pH (acidic 4.5 to 5) to dissociate ligand from receptor.

Most dissociated ligand broken down in lysosomes.

Free receptors in the CURL can recycle to membrane or be sequestered in down-regulation.

59
Q

Homologous desensitization what is it?

A

Signaling receptor is attenuated.

Can occur due to covalent modification of the ligan-bound receptor.

60
Q

Homologous Desentization, examples?

A

GPCR is desensitized upon phosphorylation of the receptor BARK (beta ARK) and then Beta Arrrestin binds to block the phosphorylated GPCR.

GPCR can be desensitized upon phosphorylation of the receptor by PKA. When the stimulated receptor activates PKA (G alpha S -> Adenylyl cyclase -> more cAMP -> activation of PKA) the activated PKA can phosphorylate the receptor and desensitize it.

61
Q

Heterologous Desensitization

A

Signaling both the stimulated receptor and by other different types of receptors is attenuated.

Both stimulated and unstimulated receptors are blocked.

Can occur due to covalent modificatin (Phosphorylation) of the receptors, or other things like competition to 2nd messengers.

Principles of Drug Action (3 decks)

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