Membrane Receptors Wk2

Question 1

Give an overview of how ligand-gated ion channels (inotropic receptors) work

Answer 1

• Binding of ACh (neurotransmitter) binds to receptor leading to ion channel opening
• Hyperpolarisation or depolarisation occurs in plasma membrane
• Causes cellular effects
• Very quick (milliseconds)
• Nicotinic
• ACh receptor

Question 2

Give an overview of how G-protein-couples receptors (metabotropic) work

Answer 2

• Sits on surface of cells (plasma proteins) therefore has ion channels or enzymes that produce soluble 2nd messengers
• G proteins mediating effects of receptors via binding and modulating effectors
• Second messages activates complex signalling cascade (longer)
• Leads to protein phosphorylation, Ca2+ release and other
• Which then has cellular effects (also caused by change in excitability bypassing second messengers)
• Takes seconds
• Muscarinic
• ACh receptor

Question 3

Give an overview of how kinase-linked receptors work

Answer 3

• Protein phosphorylation ==> Gene transcription ==> Protein synthesis ==> Cellular effects
• Mediated by gene transcription
• Takes hours
• RTKs
• Cytokine receptors

Question 4

Give an overview of how nuclear receptors work

Answer 4

• Transcription factors
• Binds to receptor in nucleus ==> Gene transcription ==> Protein synthesis ==> Cellular effects
• Hours
  Oestrogen receptor

Question 5

Facts about G protein-coupled receptors (GPCRs)

Answer 5

• Largest family of membrane receptors (approx 800) - and most important with several hormones and neurotransmitters
• 7TM domain
• Mediate effects of many hormones and neurotransmitters
• Major targets of pharmacological intervention (approx 40% of drugs on market) - drugs target these receptors

Question 6

GPCR mechanism

Answer 6

• Agonist binding
• G protein coupling and nucleotide exchange - receptor changes after binding and becomes active: GDP/GTP triggers activation of protein. Alpha and Beta gamma subunits are supposed to dissociate and alpha/beta game dimer can interact and modulate a number of factors
• Activated G protein subunits (a, B and G subunits) regulate effector proteins and ATP becomes cAMP
• Ca2+ ion channels stimulated to open
• GTP hydrolysis and inactivation of Ga protein

Question 7

What does a conformational change of receptor protein allow?

Answer 7

Allows protein to bind and then open receptor

Question 8

What do interactions between B2AR and Gs promote?

Answer 8

GDP release

Question 9

What is the effector enzyme activated by Ga(s)?

Answer 9

Adenylyl cyclase (AC)

Question 10

What is the process of ATP to cAMP with an extra O- not OH?

Answer 10

ATP + (adenylyl cyclase) ==> cAMP + (cAMP phosphodiesterase) ==> cAMP with an extra O-

Question 11

What is the process of phospholipase C (effector with two 2nd messengers)?

Answer 11

Gq ==> PLC
Phosphatidylinositol 4,5 - biphosphate(PIP2) ==> Diacylglycerol (DAG) ==> PKC
Phosphatidylinositol 4,5 - biphosphate(PIP2)==> Inositol 1,4,5-trisphosphate (InsP3) (binds to surface of channels)==> Endoplasmic reticulum (Ca2+ moves out)==> Biological response OR PKC

Question 12

Explain hormonal regulation of glycogen metabolism

Answer 12

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Question 13

What does protein kinase A do?

Answer 13

• Shuts down production of new glycogen in liver
• Initiates cascade of protein phosphorylation
• Allows glucose to enter bloodstream
• Is phosphorylated

Question 14

What does glycogen phosphorylase a (active) do?

Answer 14

Catalyses production of glucose

Question 15

What is phosphorylated in hormonal regulation of glycogen metabolism?

Answer 15

• Protein kinase A

- Phosphorylase kinase-P

Question 16

How is smooth muscle tone regulated?

Answer 16

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Question 17

What is reversibility of protein phosphorylation?

Answer 17

• Protein kinase (adds phosphate)

- Protein phosphatase (removes phosphate)

Question 18

Name GPCRs in the endocrine system

Answer 18

Hypothalamus (GHRH)
Adrenal cortex (ACTH)
Bone/muscle (GH)
Skin (MSH)
Thyroid (TSH)
Testis/ovary (LH/FSH)
Breast (oxytocin/prolactin)
Kidney (vasopressin)
PTH (kidney to bone/muscle)

Question 19

What is the cAMP/PKA pathway in endocrine cells?

Answer 19

Regulatory hormone ==> gamma beta alpha (activating and inactivating mutations ==> AC ==> cAMP + PDE(inactivating) ==> AMP ==> 2xR (inactivating mutations) + 2xC (activating mutations) ==> CREB ==>tumour development, hyper function, hormone resistance

Question 20

Explain TSH receptor signalling in the thyroid

Answer 20

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Question 21

What is TSH resistance?

Answer 21

Inactivating TSHR mutations

• Complete (homozygous muts - very rare (<1:100000, severe congenital hypothyroidism)
• Partial (heterozygous muts) (common (12% paediatric cases) mild/compensated hypothyroidism)

Question 22

What do mutations in PKA C subunit cause?

Answer 22

Adrenal Cushing’s syndrome