Receptor Transduction Systems 2

Question 1

what do GPCRs systems found in the cell membrane consist of?

Answer 1

• GPCR receptor protein itself
• G-protein (heterotrimeric, alpha-beta-gamma), alpha subunit binds GTP when active, hydrolyses to GDP to turn off signalling
• effector proteins including: enzymes, ion channels

Question 2

why do we need GPCRs?

Answer 2

they allow conserved signalling machinery to generate incredibly complex responses

Question 3

what types of responses do GPCRs allow?

Answer 3

1. amplification

2. diversity

Question 4

what does amplification consist of?

Answer 4

• one receptor may activate multiple G proteins

- one g-protein may activate multiple effector enzymes

Question 5

what does diversity consist of?

Answer 5

• a single receptor may activate different classes of G-protein with unique signalling properties
• one G-protein may activate different types of effector
• G-protein heterotrimer components: alpha and beta-gamma subunits may activate different effectors

Question 6

how are heterotrimeric G-proteins grouped?

Answer 6

they are grouped into 3 primary classes based on their downstream signalling properties

Question 7

which are the types of heterotrimeric G-proteins?

Answer 7

1. Gs family: activates cyclase to increase cAMP
2. Gi family: inhibits adenylate cyclase to decrease cAMP
3. Gq family: activates phospholipase C to produce IP3 and DAG

Question 8

what do beta-adrenoceptors do?

Answer 8

they activate adenylate cyclase: ATP–> cyclic AMP (cAMP)

Question 9

what are the effects of increased cAMP?

Answer 9

1. heart (beta1): increase heart rate and force of heart beat
2. lungs (beta2): relaxes bronchial smooth muscle

Question 10

what are the effects of agonists in the lung?

Answer 10

• dilates bronchial smooth muscle
• eases respiration
• used in asthma

Question 11

what are antagonists in the heart?

Answer 11

• competitive reversible antagonist
• slows heart rate and reduces force of beat
• used in cardiovascular disease e.g. hypertension

Question 12

what activates alpha1-adrenoceptor?

Answer 12

epinephrine

Question 13

where is alpha-adrenoceptor expressed?

Answer 13

in smooth muscle

Question 14

why does alpha-adrenoceptor couples to Gq protein?

Answer 14

because it activates PLC to generate IP3 and DAG

Question 15

how does alpha-adrenoceptor increases intracellular Ca2+ concentration?

Answer 15

by:

• release from SR (IP3)
• through membrane channels (DAG)

Question 16

what does Ca2+ do?

Answer 16

stimulates smooth muscle contraction

Question 17

what is prazosin?

Answer 17

a competitive reversible antagonist of the alpha1-adrenoceptor

Question 18

what does prazosin do?

Answer 18

prevents contraction of smooth muscle in blood vessel wall

Question 19

how does prazosin work?

Answer 19

it dilates blood vessels so blood pressure falls

Question 20

what is prazosin used for?

Answer 20

to treat cardiovascular disease e.g. hypertension

Question 21

other cell responses regulated by Gq Inositol-Phospholipid signalling

Answer 21

1. liver - vasopressin - glycogen breakdown
2. pancreas - acetylcholine - amylase secretion
3. smooth muscle - acetylcholine - contraction
4. blood platelets - thrombin - aggregation

Question 22

what is a tyrosine kinase?

Answer 22

an enzyme that can transfer a phosphate group to a tyrosine residue in a protein

Question 23

where is phosphorylation important?

Answer 23

in signal transduction to regulate enzyme activity

Question 24

what do tyrosine kinase receptors link?

Answer 24

an extracellular ligand binding domain with an intracellular tyrosine kinase domain

Question 25

what is dimerisation?

Answer 25

coupling by an agonist binding to 2 receptors

Question 26

what is a receptor tyrosine kinases (RTKs)?

Answer 26

a cell membrane receptors containing a single TM domain

Question 27

what activates RTKs?

Answer 27

hormones and growth factors e.g. insulin, AGF

Question 28

what happens when RTKs activate?

Answer 28

upon receptor activation, they form a dimer and autophosphorylate

Question 29

what happens after the formation of a dimer and autophosphorylation?

Answer 29

a kinase cascade is activates that ultimately phosphorylates a transcription factor

Question 30

what do RTKs do?

Answer 30

regulate gene expression, growth, metabolism

Question 31

examples of drugs that inhibit RTK signalling

Answer 31

1. Imatinib (Gleevec)
2. Lapatinib (tykerb)
3. Trastuzumab

Question 32

what is imatinib?

Answer 32

a small molecule tyrosine kinase inhibitor for chronic myelocytic leukemia

Question 33

what is lapatinib?

Answer 33

a small molecule EGF receptor inhibitor approved in US for breast cancer

Question 34

what is trastuzumab?

Answer 34

a monoclonal antibody against EGF used primarily again in breast cancer