Siganl Transduction (7)

Question 0

What are the three maintain types of cell surface receptors?

Answer 0

• Ligand gated
• Intrinsic enzymatic activity receptors
• G protein coupled receptors (GPCR)

Question 1

Where are the majority of receptors found and what are the anomalies?

Answer 1

• On cell surface

- Steroid and thyroid hormones are intracellular

Question 2

What is meant by an agonist to a GPCR?

Answer 2

• Binds and causes activation of a receptor

- May lead to intracellular signal transduction events

Question 3

Give examples of GPCR agonists.

Answer 3

• Anti-asthma: B2 adrenoceptor agonists

- Analgesia/anaesthesia: u-opioid receptor agonists

Question 4

What is meant by antagonists?

Answer 4

• Bind to receptor and don’t activate receptor

Question 5

Give examples of antagonists

Answer 5

• Cardiovascular: B adrenoreceptor antagonists (Beta blockers)
• Neuroleptics: D2 dopamine receptor antagonists

Question 6

When there are diseases that are associated with signal transduction what is this normally caused by in a general term?

Answer 6

• Mutations to GPCRs

Question 7

Give three examples of diseases associated with signal transduction. And what do they cause?

Answer 7

• Retiritis pigmentosa: loss of function of rhodopsin
• Nephrogenic diabetes insipidus: loss of function mutations to V2 vasopressin receptor
• Familial male precocious puberty: gain of function of LH receptor.

Question 8

Give examples of GPCRs.

Answer 8

• Sensory: light/odour/tastes
• Ion: H/Ca
• Neurotransmitter: ACh/glutamate
• Peptide and non peptide hormones: glucagon/adrenaline
• Large glycoproteins: TSH

Question 9

Outline the structure of GPCRs.

Answer 9

• Single polypeptide chain (300-1200aa)
• 7 transmembrane spanning regions
• Extracellular N-terminal
• Intracellular C-terminal
• Ligand binding regions

Question 10

What are the ligand binding regions in a GPCR?

Answer 10

• Transmembrane domain

- N-terminal region

Question 11

Once an agonist has bound to a GPCR what happens?

Answer 11

• Activated GPCR interacts with a G protein
• G protein contains alpha/beta/gamma subunits (heterotrimeric)
• GPCR-G protein interaction activates G protein by the exchange of GTP for GDP on the G protein alpha subunit
• a-BY complex dissociates into a-GTP and free BY
• These then interact with effector proteins-either 2nd messenger-generating enzymes or ion channels

Question 12

How is G-protein signalling terminated?

Answer 12

• a-GTP and BY interaction with effectors lasts until a-GTPase hydrolyses GTP->GDP
• a-GDP can then join to BY to form an inactive molecule

Question 13

What governs receptor G protein selection?

Answer 13

• Activated GPCRs preferentially interact with specific types of G protein, G-alpha subunit’s a primary determinant
• In turn, G-alpha subunits and GBY subunits interact with specific effector proteins

Question 14

Give examples of effectors of G proteins.

Answer 14

• Enzymes: adenylyl cyclase for ATP -> cAMP
• Ion channels: voltage operated Ca channels (VOCC)
  G protein-regulated inwardly-rectifying K channels (GIRKS)

Question 15

Outline the agonist stimulated regulation of adenylyl cyclase.

Answer 15

• cAMP production from ATP using adenylyl cyclase
• cAMP dependent protein kinase (PKA)
• Epacs (guanine nulceotide exchange factors)
• Cyclic-nucleotide-gated ions channels (CNGs)

Question 16

Give examples of Gs coupled receptors and what does Gs stand for?

Answer 16

• Gs: G-protein stimulatory
• B-adrenoceptors
• D1 dopamine receptors
• H2 histamine receptors

Question 17

What is meant by Gi?

Give examples of Gi-coupled receptors.

Answer 17

• G protein inhibitory
• a2 adrenoceptors
• D2 dopamine receptors
• u-opioid receptors

Question 18

How does cAMP exert the majority of its actions?

Answer 18

• Via cAMP-dependent protein kinase (PKA/A-kinase)

Question 19

Outline the agonist stimulated regulation of phospholipase C.

Answer 19

• Agonist binds to GPCR
• alpha-q GTP unit splits from BY and joins to phospholipase C
• This forms PIP2
• This then splits to form DAG and IP3
• An IP3 receptor on the Endoplasmic reticulum to stimulate the release of Ca
• Ca then joins onto PKC which binds onto the DAG molecule.

Question 20

Give examples of Gq coupled receptors.

Answer 20

• a1 adrenoceptors
• M1 muscarinic receptors
• H1 histamine receptors

Question 21

Outline how signal amplification may occur.

Answer 21

• B-adrenoceptor -> Gs protein -> adenylyl cyclase part of cascade causes little amplification
• Activation of anenylyl cyclase generates many molecules of cAMP -> activates enzyme PKA

Question 22

How can positive inotropy be caused?

Answer 22

• Adrenaline and sympathetically reused noradrenaline can interact with ventricular B1-adrenoceptors to increase force of contraction
• cAMP-dependent protein kinase stimulates VOCC channel
• Increased Ca -> increased contractility

Question 23

How does smooth muscle contract in relation to adrenoceptors?

Answer 23

• Sympathetically released NA interacts with vascular smooth muscle alpha 1 adrenoceptors -> vasoconstriction
• Parasympathetically released ACh interacts with bronchiolar smooth muscle M3-muscarinic receptors -> bronchoconstriction

Question 24

How is neurotransmitter release modulated?

Answer 24

• CNS and PNS neurotransmitter release is often modulated by presynaptic GPCR
• GBY inhibit VOCCs reducing Ca influx and neurotransmitter release