L3 - Respiration - Regulation and Control

Question 1

What 3 molecules is control of airway smooth muscle dependent on?

Answer 1

GPCR cascades including

• Gq
• Gs
• Gi

Question 2

How is airway smooth muscle controlled using Gq? - contraction

Answer 2

1. Agonist binds to receptor and stimulates G protein cascade
2. Stimulates phospholipase C
3. Production of PIP2 and IP3
4. IP3 activates cascade to release Ca from stores
5. Changes in membrane potential also open up voltage gated Ca channels
6. Activation of CaM
7. Activation of myosin light chain kinase and smooth muscle contraction

Question 3

What 3 receptors act through the Gq pathway?

Answer 3

M3 Muscarinic receptors
H1 Histamine receptors
BK bradykinin receptors

Question 4

How is airway smooth muscle controlled using Gs? - relaxation

Answer 4

1. Agonist binds to receptor and stimulates G protein cascade
2. Stimulates adenylyl cyclase
3. Production of cAMP and stimulation of PKA
4. PKA leads to smooth muscle relaxation
5. Also activates BK potassium channel which leads to cell hyperpolarisation
6. Inactivates Ca channels

Question 5

What 2 receptors act through the Gs pathway?

Answer 5

β2 Adrenergic receptors

VIP receptors

Question 6

How is airway smooth muscle controlled using Gi? - contraction

Answer 6

1. Activation of Gi receptors leads to inhibition of Adenylate Cyclase
2. Knock on effect is to counteract the stimulatory effect of Gs activation
3. Opposes the relaxation of the smooth muscle
4. Inhibits the BK channel

Question 7

Which receptor acts through the Gi pathway?

Answer 7

M2 Muscarinic receptors

Question 8

In what two ways in bronchial smooth muscle controlled?

Answer 8

Autonomic nervous system

Humoral factors

Question 9

How is bronchial smooth muscle controlled through the autonomic nervous system?

Answer 9

Parasympathetic
- Acetylcholine - released from the vagus
- Acts on muscarinic receptors leading to constriction
Sympathetic
- Norepineprine - released from nerves
- Weak agonist leading to dilation

Question 10

How is bronchial smooth muscle controlled through humoral factors?

Answer 10

Epinephrine - circulating in the blood
- Better agonist leading to dilation
Histamine – released during inflammatory processes
- Leading to constriction

Question 11

Where are receptors for parasympathetic control of lung muscle found?

Answer 11

Postganglionic Nerve - M2

Airway smooth muscle - M2 and M3

Question 12

How is muscle contraction controlled?

Answer 12

By stimulation of M3 receptors by Ach

Question 13

What is the important feedback mechanism involved in parasympathetic control?

Answer 13

Ach feeds back to M2 receptors on the postganglionic nerve to stop further release of Ach

Question 14

How are M3 receptors activated?

Answer 14

1. Myosin light chain kinase helps with cross bridge formation for muscle contraction
2. To stop contraction have to phosphorylate the myosin

Question 15

How is lung muscle sympathetically controlled?

Answer 15

Activation of β2 adrenoreceptors on airway smooth muscle

1. cAMP stimulates PKA
2. PKA decreases myosin light chain kinase activity
3. This leads to muscle relaxation

Question 16

What can asthma sufferers be triggered by?

Answer 16

Atopic (extrinsic)
- Allergies, contact with inhaled allergens
Non-Atopic (intrinsic)
- Respiratory infections, cold air, stress, exercise, inhaled irritants, drugs

Question 17

After a trigger how do asthma patient react?

Answer 17

Movement of inflammatory cells into the airways

Release of inflammatory mediators and subsequent bronchoconstriction

Question 18

What are the characteristics of an asthma patient spirometry?

Answer 18

Decrease in FEV1 (forced expiratory volume in 1 min)
Decrease in FEV1% to below 80% of tidal volume
FVC unaltered

Question 19

What is the link between M2 receptors and airway hypersensitivity?

Answer 19

Asthma is associated with an increase in parasympathetic activity
Shown as an increase in basal tone and increased muscle constriction in response to irritants

Question 20

How is the link between M2 receptors and airway hypersensitivity shown in experiments?

Answer 20

Experiments performed using animal models
- Antigen Challenge
- Viral Infection
- Ozone Exposure
- Vitamin A deficiency
All treatments produced an increase in parasympathetic activity
In all models
- No change in function of M1 or M3 receptors
- Decrease in neuronal M2 function

Question 21

What is the link between M2 receptors and asthma ?

Answer 21

In Antigen-Challenge the change in M2 function is linked to eosinophils
Eosinophils cluster around nerve fibres
Activated eosinophils release major basic protein (MBP)
MBP inhibits the M2 receptors so no negative feedback mechanism

Question 22

What are the 3 main ways to treat asthma?

Answer 22

β2 Adrenergic agonists
Anticholinergics
Glucocorticoids

Question 23

What are β2 Adrenergic agonists?

Answer 23

Short acting – Salbutamol

Longer acting – Salmeterol (delivered with corticosteroids)

Question 24

What are anticholinergics?

Answer 24

Block the effects of endogenous Ach
Inhaled daily with actions via M1 and M3 receptors
E.g. Tiotropium bromide

Question 25

What are glucocorticoids?

Answer 25

Anti-inflammatory actions
Inhaled steroids
E.g. Beclometasone