G-Protein Coupled Receptor

Question 1

Receptors

Answer 1

-Located mostly in cell membrane
-They receive messages from chemical messengers coming from other cells
-Transmit messages into the cell leading to a cellular effect
-Different receptors respond to different chemical messengers

Question 2

Neurotransmitters

Answer 2

Chemicals released from nerve endings which travel across nerve synapses to bind with receptors on target cells. They are usually short lived.

Question 3

Hormones

Answer 3

Chemicals released from cells or glands and which travel some distance to bind to receptors

Question 4

G Proteins

Answer 4

Guanine nucleotide-binding proteins are a family of proteins that act as molecular switches and are involved in transmitting signals from outside to its interior.

Question 5

How are GPCRs regulated

Answer 5

Their activity is regulated by factors that control their ability to bind to and hydrolyse guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When GTP is binded they are on and GDP is binded

Question 6

What enzymes do G proteins belong to

Answer 6

GTPases

Question 7

GPCR structure

Answer 7

3 intracellular loops
3 extracellular loops
N and C terminals

Question 8

5 different families of GPCR

Answer 8

Rhodopsin- Serotonin, dopamine
Secretin- Parathyroid hormone
Frizzled/Taster GPCR- cell differentiation and proliferation
Glutamate receptors- Modulation of excitability of synaptic cells
Adhesion class of GPCR- Cell adhesion/cell response and found in immune cells, CNS and reproductive tissue

Question 9

secondary messengers

Answer 9

cAMP system
Phosphatidylinositol system

Question 10

cAMP signal

Answer 10

-ligand binds to the GPCR
-conformational changes in the GPCR cause the G-protein complex to disassociate from GPCR
-G alpha protein and GDP are released and GTP binds to Ga protein
-The GTP/Ga binds to adenyl cyclase and activates it which produces cAMP
-The cAMP proteins binds to regulatory protein which stops it from suppressing Kinase A
-Kinase A then phosphorylates other targets

Question 11

How is CAMP system regulated

Answer 11

-Disassociation of ligand and GPCR does not stop activity
-cAMP phosphodiesterase converts cAMP to AMP which stops kinase activity
-Ga is also a GTPase which converts GTP to GDP which unbinds Ga to adenyl cyclase which stops cAMP production

Question 12

cAMP stand for

Answer 12

cyclic adenosine monophosphate

Question 13

IP3 signaling

Answer 13

-ligand binds to GPCR
-Conformational change causes G-protein complex to disassociate and the Ga and GDP are released
-Ga binds to GTP which then bind to phospholipase C which hydrolyses PIP2 releasing DAG and IP3
-IP3 causes the release of cytoplasmic calcium
-DAG activates protein kinase C whose activity is augmented by presence of Ca.

Question 14

Regulation of IP3

Answer 14

-GTPase activity of Ga halts production of IP3 and DAG
-Removal of CA by calcium ATPase pumps
DAG converted to glycerol or phosphorylated

Question 15

IP3

Answer 15

inositol-1,4,5-triphosphate

Question 16

DAG

Answer 16

diacylgylycerol

Question 17

PIP2

Answer 17

phosphatidyl-4,5-inositol biphosphate

Question 18

3 categories of GPCR

Answer 18

-agonists
-Antagonists
-Inverse agonists

Question 19

Agonist

Answer 19

–mimic natural ligand
-Binds reversibly
- similar intermolecular bonds formed as to natural messenger
-Similar structure to NM (natural messenger)
-produce same cellular response

Question 20

Example Agonist

Answer 20

Clonidine
-anxiety occurs when there is too much norepinephrine in there system
-Drug binds to alpha 2 receptor instead of norepinephrine which tricks the neuron into think there is high norepinephrine in the system which results in a negative feedback response that reduces norepinephrine production.
-less norepinephrine is the system to bind to alpha 1 on post synaptic neuron
-results in reduced nerve signals that increase heart rate and blood pressure which calms the body and so is used to treat symptoms in ADHD

Question 21

Antagonists`

Answer 21

-Bind to GPCR but does not elicit response
-Reversible binding
-Different induced fit means receptor is not activated
-No reaction takes place on antagonist
-messenger is blocked from binding site

Question 22

strength of antagonism

Answer 22

-Strength of antagonist binding and antagonist concentration

Question 23

Inverse agonists

Answer 23

-Blocks activity of endogenous ligand and produces opposite cellular response to natural ligand

Question 24

Example inverse agonist

Answer 24

Antihistamines like deselex which affects histamine receptors.
-they also affect GABA receptors

Question 25

Efficacy of agonists, antagonists, etc

Answer 25

agonist- Positive efficacy
Antagonist- zero efficacy
Inverse agonist- negative efficacy

Question 26

Difference between antagonists and inverse agonists

Answer 26

Antagonists binds to receptor but does not reduce basal activity

Question 27

Most important factor for GPCR drugs

Answer 27

Compounds that modulate GPCR activity must be able to adopt the specific conformation required by the binding site in order to propagate a signal in the cell to have a desired effect.
Histamine has a very different shape to Claritin