Cell Signaling

Question 1

What are the three mains steps of cell signaling?

Answer 1

1. Reception: Ligand binds with receptor
2. Transduction: Signaling cascade
3. Cell Response: Response within the cell

Question 2

What are the 4 main classes of receptors?

Answer 2

• Ion Channels
• G-Protein Coupled Receptors (GPCRs)
• Kinase or Kinase Associated Receptors
• Intracellular Receptors

Question 3

Ion Channel

Answer 3

• Binding of ligand allow ions to cross membrane, can:
  
  • Changes membrane potential
  • Activate signal proteins or channels
  • Release intracellular calcium
• Examples:
  
  • Acetylcholine receptors on muscle
  • GABA A receptors

Question 4

G-Protein Coupled Receptors are ____-transdomain receptors

Answer 4

G-Protein Coupled Receptors are 7-transdomain receptors

Question 5

G-Protein Coupled Receptors (GPCRs)

Mechanism of Action

Answer 5

• Ligand binding activates associated G protein (trimers with a, b, and y components)
• When activated the alpha component binds GTP, dissociates, and activates an enzyme

Question 6

What are the three classes of G-protein alpha subunits

Answer 6

q

i

s

Question 7

GPCR: Gs

Mechanism of Action

Examples

Answer 7

Mechanism of Action (s stimulates PKA):

• S activates adenylate cyclase
• Adenylate cyclase produces cAMP
• cAMP activates Protein Kinase A (PKA)

Examples of Gs GPCRs:

• Serotonin R 4, 6, 7
• Histamine H2 R
• Prostoglandin I₂ R
• Calcitonin R

Question 8

GPCR: Gi

Mechanism of Action

Examples

Answer 8

Mechanism of Action (i inhibits PKA):

• i inhibits adenylate cyclase
• Leads to decrease of cAMP
• Leads to decreased activity of Protein Kinase A (PKA)

Examples:

• Norepinephrine a2 R
• Adenosine A₂ R
• Glutamate R 2-3, 6, 8
• GABA B Receptor

Question 9

GPCR: Gq

Mechanism of Action

Examples

Answer 9

Mechanism of Action:

• q activates PLC
• PLC cleaves PIP₂ to make IP₃ and DAG
• IP₃ releases intracellular Ca2+ from the ER
• DAG and Ca2+ activate Protein Kinase C (PKC)

Examples:

• Norepinephrine a1 R
• Anngiotensin II R (AT₂)
• Vasopressin R (V1)

Question 10

Receptor Tyrosine Kinase (RTK)

Mechanism of Action

Examples

Answer 10

Mechanisms of Action:

• Ligand binds –> receptor dimerizes
• Receptors phosphorylate eachother at Tyrosine residues
• Recruits SH proteins:
  
  • Enzymes: Src, PLC
  • Adaptors: SOS
• SOS activates the RAS Enzyme
  
  • RAS activates RAF which is a MAPKKK that acts in the MAP Kinase Cascade

Examples:

• Insulin
• VEGF and FGF
• BDNF

Question 11

MAP Kinase Cascade

Answer 11

• Series of kinases downstream of RTKs
• Phosphorylation acts as an on/off switch
• RAS activates RAF
• RAF is a MAPKKK that activates MEK which is a MAPKK
• MEK activates ERK which is a MAPK
• ERK acts on multiple targets

Question 12

RTK Example: Insulin Receptor

Mechanism of Action

Cell Response

Answer 12

Mechanism of Action:

• Receptor is a tetramer at start (2a and 2b)
• Insulin binds –> Receptors phosphorylate eachother at Tyrosine residues
• Receptors phosphorylate IRS and SHC proteins
• IRS activates enzyme to make PIP₃
• PIP3 works with a kinase to activate AKT
• Additionally SHC leads to activation of RAF

Cell Response:

• Glucose transport proteins (GLUTs) are expressed on cell membrane
• Glycogen storage increases
• Protein synthesis increases

Question 13

Serine-Threonine Kinase

Mechanism of Action

Examples

Answer 13

Mechanism of Action

• Ligand binds –> Receptor dimerizes
• Receptors phosphorylate each otheron serine or threonine residues
• SMAD binds and gets phosphorylated
• SMAD binds co-SMAD, and this SMAD complex enters the nucleus and changes gene expression

Examples:

• TGF-B
• Tumor Necrosis Factor
• BMP

Question 14

JAK-STAT

Mechanisms of Action

Examples

Answer 14

Mechanisms of Action:

• Ligand binds –> receptor dimerizes
• JAK proteins bind and phosphorylate each other and the receptor
• STAT proteins bind and get phosphorylated
• STATs dimerize, enter nucleus, and change gene expression

Examples:

• TINs: erythropoietin, thrombopoietin, prolactin
• TERs: interluekins, interferons (cytokines)
• Growth Hormone
• GM-CSF

Question 15

Intracellular Receptors

Mechanism of Action

Examples

Answer 15

Mechanisms of Action

• Ligand diffuses across the membrane (hydrophobic)
• Binds to receptor inside the cell
• Translocated to nucleus to change gene expression

Examples

• Cortisol
• Testosterone and Estrogen
• Aldosterone and Vitamin D

Question 16

What are the 3 mechanisms to turn off cell receptor signaling?

Answer 16

• Phosphatases
  
  • Enyzmes that remove phosphates from proteins, effectively turning them off
• Degredation
  
  • Receptors or signal proteins are tagged with ubiquitin for proteasome desctruction
  • cAMP/cGMP degraded by phosphodiesterase enzymes inside the cell
• Desensitization
  
  • ​Ligand-bound receptors internalize and are degraded by lysosomes
  • Endoyctose receptors into vesicles to prevent ligand binding
  • Cell reduces number of receptor proteins by decreasing gene expression

Question 17

Ionotropic Receptors vs Metabotropic Receptor

Answer 17

Ionotropic receptors direcetly open ion channels when activated

Metabotropic receptors are G-protein coupled receptors and have many possible effects. One possible effect is they can indirectly open ion channels when activated through the use of second messengers