Signaling Mechs.. Regulating Cell to Cell Communication

Question 1

Goal of creating drugs is to:

Answer 1

1. Bind to the receptor or destroy associated proteins

Question 2

General mech of ion channels. They pass ions:

Answer 2

Down chemical gradient. Ligand bind to receptor and ions flow through

Question 3

Oligomeric channel:

Answer 3

They bind to another protein. If you mess up one subunit, the channel and protein both suffer.

Question 4

Gist of Cystic Fibrosis:

Answer 4

CFTR gene = Cl- channel. Disease is AR. Disease = loss of function of this gene. Causes abnormal salt transport across epithelial cell membranes, leading to thick mucus buildup in respiratory epithelial cells.

Question 5

CFTR ligand:

Answer 5

ATP

Question 6

What likely happens upon tampering Na+ channel?

Answer 6

paramyotonia, cardiac arrhythmia, epilepsy

Question 7

Tetrodotoxin:

Answer 7

Na+ channel blocker. Comes from pufferfish. Screws with action potential. Irreversible binding

Question 8

General gist of Nuclear Steroid Hormone Receptors

Answer 8

Ligand = steroid (hormone), which passes through membrane. Still needs receptor to do job (Act as Transcription factor)

Question 9

Receptor location in Nuclear Steroid Hormone Receptor:

Answer 9

cytosol or nucleus (usually cytosol)

Question 10

Steps to Nuclear Steroid Hormone Receptors:

Answer 10

1. Hormone passes through membrane. Binds to receptor, causing CHAPERONE to dissociate from receptor.
2. Receptor-ligand complex follow nuclear localization sequence (get into nucleus)
3. Entire complex binds to hormone receptor element (HRE). Causes gene transcription

Question 11

Concern with breast cancer and treatment:

Answer 11

1. Over expression of estrogen receptors
2. Endocrine Therapy works by binding antagonists to estrogen receptor to prevent estrogen from binding.
   Tamoxifen = Antagonist (tamoxifen metabolizes to hydroxytamoxifen, which does the actual binding)

Question 12

General gist of Protein kinase Receptors (PKR)

Answer 12

transmembrane receptor that works by transferring P from high energy molecules (ATP) to target molecules in cytoplasm.

Question 13

Difference between phosphatase and kinase

Answer 13

Kinase = adds P. PhosphaTase = Takes away P

Question 14

Protein Kinase Receptor Mech (S/T Kinase)

Answer 14

1. ligand binds to EACH ECM (Extracellular membrane (ECM) component.
2. Kinase is activated. Phosphorylation chain runs all the way through into cytoplasmic domain.
3. Cytoplasmic domain units dimerize now that they are self-phosphorylated
4. Cytoplasmic proteins are recruited to it.
   Note: Phosphorylation IS reversible (phosphatase)

Question 15

What interacts with cytoplasmic (“Docking”) component of Protein Kinase Receptors? What additional unit needs to bind in case of Y kinase?

Answer 15

1. Grb

2. SH2-Domain, which recognizes phosphorylated Y.

Question 16

What binds to Grb? What does it do?

Answer 16

1. GEF (Guanine nucleotide exchange factor). SoS is an example of this.
2. Activates G-proteins like Ras by GEFs switching GDP for GTP

Question 17

What is a GAP (GTPase Activating Protein)?

Answer 17

Inactivates G-protein by switching GTP for GDP.

Question 18

What is a G-protein?

Answer 18

It binds GEFs to act as a switch

Question 19

Why is Ras so important?

Answer 19

Acts as convergence of multiple signal pathways like MAPK

Question 20

Link Ras to cancer:

Answer 20

Upon mutation, all downstream mutations would be turned on because Sos (a GEF) would be unable to convert GTP to GDP

Question 21

What’s up with Neurofibromatosisn Type-1?

Answer 21

NF1 gene, which encodes Ras GAP is mutated. Ras is always one since GAP is not able to convert GTP to GDP

Question 22

What is the deal with Noonan Syndrome?

Answer 22

PTPN11 gene mutation, which is responsible for SHP2. Mutation overactivates Ras

Question 23

What is the gist of 7-alpha helix receptors?

Answer 23

Most prominent receptor. used for the senses. Ligand binding converts GDP to GTP, activating it.

Question 24

Sample 7-alpha helix receptor mech (PKA) to release Ca2+ from cytoplasm

Answer 24

1. ligand binds, converting GDP to GTP.
2. Cytoplasmic domain splits G-alpha from beta-gamma subunit.
   3a. Gs-alpha or Gi-alpha triggers adenylate cyclase (AC)
3. AC converts ATP to cAMP
4. cAMP turns on PKA
5. PKA releases tone of Ca2+ stored in SER

Question 25

Sample 7-alpha helix receptor mech (PKC)

Answer 25

1. ligand binds, converting GDP to GTP.
2. Cytoplasmic domain splits G-alpha from beta-gamma subunit.
   3a. Gq-alpha triggers PLC
3. PLC converts PiP2 to iP3 and DAG
4. iP3 cuases Ca2+ release from SER
5. DAG binds to C1, Ca2+ binds to C2. PKC is now turned on. Activation is permanent (fact check this)

Question 26

How does Calmodulin work?

Answer 26

4 Ca2+ inds to it to activate it. Now, it can activate calmodulin activated prtein kinase (CAMK). Mess with CAMKII = Alzheimer’s Disease