Respiration III

Question 1

What controls the diameter of the lumen of the airways?

What is this dependant on?

Answer 1

Airway smooth muscle

Dependant on GPCR cascades that make the muscle contract/relax

Question 2

How is the overall relaxation/contraction state of the airway smooth muscle determined?

Answer 2

By the OVERALL activation fo the 3 GPCR cascades:

• Gq
• Gs
• Gi

Question 3

What are the receptors of the Gq pathway?

Answer 3

• M3 muscarinic
• H1 histamine
• BK bradykinin

Question 4

What is the Gq pathway linked to?

Answer 4

Airway CONSTRICTION

Question 5

What is the Gq pathway that stimulates airway CONTRACTION?

Answer 5

1) Agonist binds to the receptor and activates G protein Gq
2) Gq stimulates PHOSPHOLIPASE C
3) PIP2 splits into DAG and IP3
4) IP3 activates the cascade - releases calcium from stores
5) Changes to the membrane potential - open Ca2+ voltage gated channels
6) Influx of calcium across the cell membrane
7) Smooth muscle contraction

Question 6

What are the receptors that activate the Gs pathway?

Answer 6

• Beta2 adrenergic receptors

- VIP receptors

Question 7

What is stimulation of the Gs pathway linked to?

Answer 7

Airway RELAXATION

Question 8

What is the Gs pathway that stimulates airway RELAXATION?

Answer 8

1) Activate G2 subunit
2) Stimulate ADENYLATE CYCLASE
3) Production of cAMP
4) Stimulation of protein kinase A
5) PKA leads to phosphorylation
6) Leading to smooth muscle relaxation

Question 9

As well as activating adenylate cyclase, what else does Gs do?

What does this lead to?

Answer 9

Activate the BK K+ channel:

1) K+ out of the cell - hyperpolarisaion (more negative inside)
2) INACTIVATES Ca2+ channels
3) Membrane is FURTHER AWAY for VG Ca2+ channels to open - preventing muscle contraction

Question 10

What are the receptors acting through the Gi pathway?

Answer 10

M2 muscarinic receptors

Question 11

What does the Gi pathway lead to?

What does this cause?

Answer 11

INHIBITION of ADENYLATE CYCLASE

• Counteracts the stimulatory effect of Gs activation (normally relaxes the airways)
• OPPOSES smooth muscle relaxation

Question 12

As well as inhibiting adenylate cyclase, what else does Gi do?

What does this lead to?

Answer 12

INHIBITS the the BK K+ channel

1) K+ DOESN’T move out of the cell
2) Membrane potential is MORE positive - MORE chance of Ca2+ channels being open

Question 13

What are the 3 controls of of the airway smooth muscle?

Answer 13

1) Sympathetic nervous system
2) Parasympathetic nervous system
3) Humoral factors

Question 14

How does the sympathetic nervous system control the smooth muscle of the airways?

Answer 14

Release of NOREPINEPHRINE

Leads to DILATION

Question 15

How does the parasympathetic nervous system control the smooth muscle of the airways?

Answer 15

Release of acetylcholine from the VAGUS NERVE

Leads to CONSTRICTION

Question 16

What receptors does Ach from the vagus nerve act on?

Answer 16

Muscarinic receptors

Question 17

What HUMORAL factors control the smooth muscle of the nervous system?

Answer 17

1) Epinephrine - leads to DILATION

2) Histamine - leads to CONSTRICTION

Question 18

When is histamine released?

Answer 18

During inflammatory responses

Question 19

How does histamine lead to constriction?

Answer 19

• Activation of the H1 receptor

- Activates the Gq pathway

Question 20

Where are the receptors involved in parasympathetic control present?

Which receptors control smooth muscle contraction?

Answer 20

1) Postganglion neurons
- M2 receptors

2) Airway smooth muscle (target)
- M2 and M3 receptors

M3 receptors control smooth muscle contraction

Question 21

What is the negative feedback in the control of smooth muscle contraction in parasympathetic control?

Answer 21

1) Ach released from postganglionic nerve
2) SOME Ach travels across the cleft and activates M3 receptors
3) SOME Ach feedback on the M2 receptors on the postganglionic nerve - preventing further release of Ach

Question 22

What happens if the feedback mechanism in the parasympathetic control of smooth muscle is disrupted?

Answer 22

Leads to ASTHMA and HYPERSENSITIVE airways

Question 23

What happens when the M3 receptors are activated through parasympathetic control?

Answer 23

Contraction of the brachial smooth muscle:
1) Ach bind to M3 receptors - activating the Gq pathway

2) Increase in intracellular Ca2+ (through activation of phospholipase C, IP3 formation from PIP2 etc.)
3) Ca2+ bind to CaM to form Ca2+/calmodulin
4) Ca2+/calmodulin binds to myosin light chain kinase (MLCK) - allowing another kinase to phosphorylate MLCK to activate it
5) MLCK phosphoylates the myosin light chain
6) Cross-bridge formation formed by the myosin
7) Contraction of the smooth muscle

Question 24

What happens at the same time as the Gq pathway in smooth muscle contraction in the airways?

Answer 24

Protein kinase C (PKC) phosphylates and INHIBITS myosin light chain PHOSPHATASE

–> PREVENTING relaxation of the muscle

Question 25

How is contraction of the airway smooth muscle stopped?

Answer 25

By allowing activation of MLCP - can remove the phosphate from the myosin chain and prevent cross-bridge formation

Question 26

What is a beta2 adrenoreceptor agonist? What happens when it binds to B2 adrenoreceptors?

Answer 26

Salbutamol When bind: - Activate the receptor - Activate the Gs pathway - Activating PKA (through activation of adenylate cyclase and cAMP)

Question 27

What does PKA phosphorylate to induce smooth muscle relaxation? What does this cause?

Answer 27

Phosphorylates MLCK at a DIFFERENT SITE to PKC Causes a REDUCTION in the activity of MLCK

Question 28

What does the reduction of Ca2+ inside the cell (through the activation of BK K+ channels in muscle relaxation) cause?

Answer 28

- Turns off Ca2+/CaM signalling | - Inactivates MLCK

Question 29

At the same time as the activation of B2 adrenoreceptors by the SNS to increase muscle relaxation, what also occurs? What does this cause

Answer 29

1) Activation of BK K+ channels 2) Stimulation of MLCP - Dephosphorylation of myosin light chain - Loss of cross linking

Question 30

What is asthma caused by?

Answer 30

Hypersensitive airways Due to the increase in parasympathetic activity and M2 receptors

Question 31

What are the 2 triggers for asthma?

Answer 31

1) Atopic (extrinsic) | 2) Non-atopic (intrinsic)

Question 32

What are the atopic triggers of asthma?

Answer 32

Allergens/allergies

Question 33

What are the non-atopic triggers of asthma?

Answer 33

- Respiratory infections - Stress - Cold air - Exercise - Inhaled irritants

Question 34

What is the response in asthma?

Answer 34

1) Movement of inflammatory cells into the airways 2) Release of inflammatory mediators 3) BronchoCONSTRICTION

Question 35

What are the inflammatory mediators released from inflammatory cells during asthma?

Answer 35

Histamine

Question 36

Describe the spirometry in asthma

Answer 36

- VC (vital capacity) in NORMAL range - FEV1 (forced expiratory volume in one second) is <80% of FVC (forced vital capacity) - Reduction in FEV1% (Final volume is the SAME, but takes LONGER to expel the air)

Question 37

How are hypersensitive airways caused?

Answer 37

- Inhibition of the negative feedback of Ach on the M2 receptors - More Ach released - Hypersensitivity

Question 38

What does hypersensitivity affect the muscles of the airways?

Answer 38

Increases BASAL TONE | Increases MUSCLE CONSTRICTION in response to irritants

Question 39

In the antigen-challenge, what is the change in M2 function linked to? How?

Answer 39

Eosinophils: - Cluster around the nerve fibres - Activated eosinophils release major basic protein (MBP) - MBP acts as an AGONIST and inhibit the M2 receptors - INHIBITS negative feedback - Overproduction of Ach and airway oversensitivity - Over contraction

Question 40

What does ozone exposure cause?

Answer 40

Activation of the eosinophil pathway: - Synthesis of MBP - Inhibition of receptors

Question 41

What does virus exposure cause the activation of?

Answer 41

- Macrophages - Neuraminidase - Interferons

Question 42

What does the activation of neuraminidase cause?

Answer 42

Cleavage of part of the M2 receptor and changes to the binding affinity for Ach

Question 43

What does the activation of interferons cause?

Answer 43

Reduced M2 gene expression

Question 44

How are cases of asthma REDUCED in diabetics?

Answer 44

Insulin reduces M2 receptors Reduced insulin in diabetics

Question 45

What are 3 treatments for asthma?

Answer 45

1) Beta2 adrenergic agonists 2) Anticholinergics 3) Glucocorticoids

Question 46

What do Beta2 adrenal agonists do?

Answer 46

Acitvate the Gs pathway

Question 47

What are the shorter acting Beta2 adrenal agonists?

Answer 47

Salbutamol

Question 48

What are the longer acting Beta2 adrenal agonists? What must this be delivered with?

Answer 48

Salmeterol Delivered with corticosteroids

Question 49

What do anticholinergics do?

Answer 49

- BLOCK the effects of Ach on the M3 receptor - Preventing activation of the Gq pathway - Causing airway relaxation

Question 50

What do glucocorticoids do?

Answer 50

Anti-inflammatory: - Prevent the binding of eosinophils to the nerve terminals - Upregulate anti-inflammatory genes - Inhibit inflammatory genes