Lecture 20

Question 1

3 ways of cellular communication

Answer 1

1. synaptic signaling (neurotrasnmitter)
2. endocrine signaling (hormone)
3. direct contact (paracrine or autocrine) e.g. thromboxane

Question 2

2 types of receptor

Answer 2

1. Intercellular receptor
   - on cell surface, which produce secondary messengers and thus signal transduction cascade
2. Intracellular receptor
   - bind to cytosolic protein receptor or DNA sequence

Question 3

2 ways that hormone can be released

Answer 3

1. Endocrine - directly into bloodstream

2. Exocrine - first secreted into duct and then into bloodstream

Question 4

How is hormone controlled? (2)

Answer 4

1. Coordinated counter-regulatory of opposing pathways (Gs and Gi)
2. Antagonistic action of other hormone
   eg. insulin and glucagon

Question 5

What is Bmax?

Answer 5

max hormone binding (analogue to Vmax)

Question 6

What is Kd?

Answer 6

dissociation constant of receptor-hormone complex (same as half the receptors which have formed receptor-hormone complex) = 1/2Bmax (analogue to Km)

Question 7

How is cascade reaction switched off? (2)

Answer 7

1. hormone will dissociate from membrane receptor and removed from circulation by liver.
2. Then cAMP is degraded by phosphodiesterases producing AMP.

Question 8

How can cAMP degradation be inhibited?

Answer 8

Phosphodiesterase inhibitors such as methylxanthine can be used which potentiates the effect of cAMP

Question 9

4 Principle groups of receptors

Answer 9

1. Type 1 : Ligand-gated ion channels
2. Type 2: G-protein-coupled receptors (GPCR)
3. Type 3: Enzyme-linked receptor (tyrosine kinase)
4. Type 4 : Steroid hormone receptors

Question 10

Example of Type 1 receptor

Answer 10

nicotinic cholinergic neuroreceptors

Question 11

Mechanism of type 1 receptor

Answer 11

Binding of neurotransmitter opens the receptor, allowing a rapid influx of ions into cytoplasm. When terminating signal, the neurotransmitter at synaptic cleft is cleaved or degraded by enzyme (eg acetylcholinesterase)

Question 12

Structure of Type2 receptor (3)

Answer 12

GPCR contain 7 transmembrane alpha helices (heptahelical receptor)
Extracellular domain interact with ligand (hormone or neurotransmitter)
Intracellular domain interact with G proteins.

Question 13

Mechanism of type2receptor

Answer 13

1. Ligand binds to receptor which cause GTP to bind to G protein alpha subunit, causing conformational change.
2. As a result, alpha subunit of G protein dissociates from beta and gamma subunits, then activates adenylyl cyclase, which convert ATP to cAMP.

Question 14

Glucagon interaction with GPCR

Answer 14

1. glucagon binds to GPCR which cause GTP to bind to G protein alpha subunit, causing conformational change.
2. Alpha subunit of G protein dissociates and activates adenylyl cyclase which turns ATP to cAMP.
3. cAMP then activates protein kinase A which stimulates glycogenolysis and inhibits hepatic glycolysis (inhibit pyruvate kinase by phosphorylating it)

Question 15

2 ways of termination of glucagon

Answer 15

1. Hydrolysis of GTP

2. Hydrolysis of cAMP to AMP by phosphodiesterase

Question 16

2 ways G-protein can activate other protein

Answer 16

1. Gs activates adenylyl cyclase which convert ATP to cAMP
2. Gq activates phospholipase C which react with PIP2 (localized inner membrane leaflet of membrane), producing IP3 (produced to cytoplasm) and DAG (produced in membrane)

Question 17

Which type of G protein is linked with beta 1 receptor

Answer 17

Gs linked with B1 Receptor

Question 18

Which type of G protein is linked with alpha 1 receptor?

Answer 18

Gq linked with alpha 1 receptor

Question 19

Which type of G protein is linked with alpha 2 receptor?

Answer 19

Gi (inhibitory) linked with alpha 2 receptor

Question 20

What does Gq protein activate?

Answer 20

Phospholiapse C > PIP2 >IP3+DAG

Question 21

What does Gs protein activate?

Answer 21

activate adenyly cyclase

Question 22

What does Gi protein activate?

Answer 22

inhibit adenylyl cyclase by replacing GTP with GDP

Question 23

Epinephrine has higher affinity for Beta or alpha receptor?

Answer 23

Beta1 receptor

Question 24

Norepinephrine primarily acts through which receptor?

Answer 24

alpha receptor

Question 25

Effect of IP3

Answer 25

Increase calcium influx causing smooth muscle contraction

Question 26

Effect of DAG

Answer 26

activate PKC

Question 27

Effect of activation of Gi (3)

Answer 27

1. inhibit adenylyl cyclase leading decrease cAMP 2. Increased opening of K+ channel, leading to membrane hyperpolarization 3. increased closing of neuronal calcium channel, leading to decreased NE release from nerve terminal

Question 28

What is difference between beta 1 and beta 2 receptor?

Answer 28

beta 2 is more specific to epinephrine while beta 1 has equal binding to epinephrine and norepinephrine

Question 29

Effect of binding of epinephrine to beta-adrenergic receptors on skeletal myocytes (2)

Answer 29

- stimulate glycogenolysis | - inhibit glycogenesis

Question 30

Factors that affect arterial BP

Answer 30

Cardiac output (heart rate, stroke volume) peripheral resistance

Question 31

What is Type 3 receptor made up of?

Answer 31

single transmembrane protein Kinase

Question 32

How does Type 3 receptor work?

Answer 32

1. hormone binds to receptor which activates protein kinase that phosphorylates intracellular proteins.

Question 33

Mechanism of insulin receptor

Answer 33

1. insulin binds to receptor which activates tyrosine kinase activity in intracellular domain of Beta subunit. 2. Then, tyrosine residue of beta subunit are autophosphorylated. 3. Then, tyrosine kinase phosphorylates tyrosines in other proteins such as insulin receptor substrates (IRS). 4. Phosphorylated IRS promote activation of protein kinases and phosphatases, leading to the metabolic effects of insulin.

Question 34

What is insulin receptor made up of?

Answer 34

two alpha and two beta subunits alpha subunits held by disulfide bond induce conformational change that stimulates tyrosine kinase acitvity of beta subunit.

Question 35

Effects of insulin (3)

Answer 35

- rapid increase in glucose transport into cytoplasm of adipose and muscle tissue - stimulate transcription of specific genes for glycolytic enzyme such as hepatic glucokinase & phosphofructokinase - activate lipogenesis in adipocytes and inactivate lipolysis

Question 36

What is difference between lipid-soluble hormones (type 4 receptor) to other types of signals?

Answer 36

- target intracellular receptors which bind to regulatory regions of DNA that induce or repress specific genes. - have longer half life

Question 37

Mechanism of cortisol receptors

Answer 37

1. Cortisol binds to cortisol receptors in cytosol which leads to dissociation of Hsp from receptor (Usually bound to receptor to make it inactive) 2. Activated receptor then homodimerize and translocate to nucleus where they bind to DNA at hormone response element (HRE) in the promoter region, controlling gene expression. 3. Thus it increase transcription of gluconeogenic enzyme.

Question 38

Why does steroid hormones have similar structures with minor changes bring about different cellular function?

Answer 38

Because they bind to different receptors which causes different cellular function e.g. testosterone and progesterone (male/female)