Exam 2 (Lecture 14)

Question 1

Receptor Superfamilies

Answer 1

Nuclear Receptors
Receptor Tyrosine Kinases (RTK)
Cytokine Receptors
Ligand-gated Ion Channel receptors
G protein-coupled Receptors (GPCR)

Question 2

Receptor Confirmations

Answer 2

2 Interconvertible confirmations
Active vs Inactive
Ligand doesn’t induce confirmation change, it locks its confirmation.

Question 3

Nuclear receptors:

Physiological function and categorization

Answer 3

Ligands tend to be lipophilic

Regulate expression of specific genes

Participate in control of development, homeostasis and metabolism

Can directly bind DNA; classified as transcription factors

Receptors reside in either the cytoplasm or nucleus, in a complex with chaperone proteins (e.g., HSP90), and upon binding agonist the chaperones dissociate and receptors DIMERIZE either with themselves (homodimers) or another nuclear receptor (heterodimers).

Receptor dimers bind to specific sites on DNA (promoter regions) designated as HREs with palindromic sequences (e.g. ATTCGGCTTA) which bind dimeric receptors and facilitate binding of other transcription factors

Question 4

HRE

Answer 4

Hormone-responsive elements

Question 5

Steroid receptors

Answer 5

Estrogen
Androgen
Glucocorticoid (cortisol)
Mineralcorticoid (aldosterone)
Vitamind D

Question 6

Representative Therapeutics

Answer 6

Enzalutamide - prostate cancer
Tamoxifen - breast cancer
Lipaglyn - type II diabetes
Cortisone - anti-itch and pain relief

Question 7

glucocorticoids

Answer 7

controls metabolism and decrease inflammation

used to treat allergies, asthma, autoimmune diseases, sepsis; lymphomas and leukemias

Question 8

BDNF

Answer 8

Pain and neuronal disease

Question 9

GDNF

Answer 9

Gene therapy for Parkinson’s disease

Question 10

Infliximab

Answer 10

antibody that neutralizes TNF alpha and treats Crohn’s disease

Question 11

Etanercept

Answer 11

fusion protein that works as TNF alpha inhibitor and treats arthritis

Question 12

STAT protein

Answer 12

binds to sites called GAS (Gamma-activated-sites) in the promoter region of cytokine inducible genes and activates transcription

nuclear phosphatases can inactivate

Question 13

Natural ligands

Answer 13

acetylcholine, serotonin, GABA, glutamate

Question 14

Pentameric cys-loop cationic receptors ( 5 subunits)

Answer 14

5-HT, nicotinic acetylcholine

Question 15

Pentameric cys-loop anionic receptors (5 subunits)

Answer 15

GABAA, Glycine

Question 16

Ionotropic glutamate receptors (cation, 4 subunits)

Answer 16

AMPA, Kainate, NMDA

Question 17

P2X purinoreceptors (cation)

Answer 17

3 subunits

Question 18

Benzodiazepines

Answer 18

positive allosteric modulators, enhance effect of GABA at GABAa receptor

Question 19

Barbiturates

Answer 19

Same effects as benzodiazepine but more toxic so been replaced

Question 20

Classes of G proteins

Answer 20

GTPi, GTPq,GTPs, GTP12

Question 21

GTPi

Answer 21

Inhibition of cAMP production, ion channels, phosphodiesterase, phospholipases

Question 22

GTPq

Answer 22

increase IP3 -> increase CA2+

Increase DAG -> increase Protein Kinase C

Question 23

GTPs

Answer 23

increase in cAMP concentration

Question 24

GTP12/13

Answer 24

RhoGEF -> RhoA -> ROCK

Question 25

Gs vs Gi effects

Answer 25

Gi and Gs regulate the Adenylate Cyclase/cAMP/PKA signaling pathway
Norepinephrine (alpha receptor) inhibit pathway(Gi)
Epinephrine (beta receptor) active pathway (Gs)

alpha receptor = gi
beta receptor = gs

Question 26

Gq pathway

Answer 26

Gq -> PLC -> PIP2 -> IP3 -> Ca2+ -> Calmodulin Binding enzymes

Gq -> PLC -> DAG -> PKC -> Kinase cascade

Question 27

G protein activation cycle

Answer 27

Agonist activates the receptor, which promotes the release of GDP from the G protein.

This allows entry of GTP into the nucleotide binding site.

In its bounds state, the G protein regulates activity of an effector enzyme or ion channel.

Signal is terminated by hydrolysis of GTP, followed by return of the system to the basal unstimulated state.

Question 28

Rapid desensitization

Answer 28

Exposure of cells to agonist produces cAMP response.

reduced response observed in continued presence of agonist (desensitization) occurs in a few minutes.

If agonist is removed after short time, cells can recover to full responsiveness to another addition of agonist (resensitization)

This resensitization fails to occur, or occurs incompletely if cells are exposed to agonist repeatedly or over a more prolonged time period.

Re

Question 29

Down regulation of B adrenoreceptors

Answer 29

1. Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins in cytoplasm
2. Agonost-activated proteins are phosphorylated by GRK, preventing interaction with Gs and promoting binding of B-arrestin.
3. Receptor-arresting complex binds to coated pits, promoting internalization.
4. Agonist dissociates from internalized receptor, Redding affinity for B-arrestin and allows for dephospho rylation by P’ase and return receptor to membrane. This is resensitization.
5. repeated or prolonged exposure of cells to agonist favors the delivery of internalized receptors to lysosomes, promoting down-regulation instead of resensitization.

Question 30

Key Steps in Signal Transduction

Answer 30

1. release of primary messenger, GPCR ligand
2. reception of primary messenger, signal molecule binds to receptor
3. relay: modulation by other factors
4. Amplification
5. Delivery of the message inside the cell by 2nd messenger to multiple targets.

Question 31

Second messangers

Answer 31

cGMP, cAMP, IP3, DAG, calcium, Nitrix Oxide (NO)

Signal can be amplified,
can be stored in organelles
Common second messengers may create “cross talk”

Question 32

cAMP downstream resposne

Answer 32

Once cAMP is made, it binds to Protein Kinase A

C subunit gets released and goes into nuclease, activates transcription factor (CREB)

Plays a role in memory and learning

Question 33

Inhibition Mechanism for downstream response

Answer 33

Phosphatases: Takes away phosphorylation (dephosphorylation)

Phosphodiesterase (PDE): inhibitor for cAMP

Question 34

Interactions with other receptors

Answer 34

GPCR can directly (via G protein) or indirectly (via second messenger) gate ion channels

RTKs can also gate ion channels

Question 35

Class A vs Class C G-protein receptors

Answer 35

Class A: for Neuropharmacology do not dimerize

Class C: dimerize