L3 - Respiration - Regulation and Control Flashcards
What 3 molecules is control of airway smooth muscle dependent on?
GPCR cascades including
- Gq
- Gs
- Gi
How is airway smooth muscle controlled using Gq? - contraction
- Agonist binds to receptor and stimulates G protein cascade
- Stimulates phospholipase C
- Production of PIP2 and IP3
- IP3 activates cascade to release Ca from stores
- Changes in membrane potential also open up voltage gated Ca channels
- Activation of CaM
- Activation of myosin light chain kinase and smooth muscle contraction
What 3 receptors act through the Gq pathway?
M3 Muscarinic receptors
H1 Histamine receptors
BK bradykinin receptors
How is airway smooth muscle controlled using Gs? - relaxation
- Agonist binds to receptor and stimulates G protein cascade
- Stimulates adenylyl cyclase
- Production of cAMP and stimulation of PKA
- PKA leads to smooth muscle relaxation
- Also activates BK potassium channel which leads to cell hyperpolarisation
- Inactivates Ca channels
What 2 receptors act through the Gs pathway?
β2 Adrenergic receptors
VIP receptors
How is airway smooth muscle controlled using Gi? - contraction
- Activation of Gi receptors leads to inhibition of Adenylate Cyclase
- Knock on effect is to counteract the stimulatory effect of Gs activation
- Opposes the relaxation of the smooth muscle
- Inhibits the BK channel
Which receptor acts through the Gi pathway?
M2 Muscarinic receptors
In what two ways in bronchial smooth muscle controlled?
Autonomic nervous system
Humoral factors
How is bronchial smooth muscle controlled through the autonomic nervous system?
Parasympathetic
- Acetylcholine - released from the vagus
- Acts on muscarinic receptors leading to constriction
Sympathetic
- Norepineprine - released from nerves
- Weak agonist leading to dilation
How is bronchial smooth muscle controlled through humoral factors?
Epinephrine - circulating in the blood
- Better agonist leading to dilation
Histamine – released during inflammatory processes
- Leading to constriction
Where are receptors for parasympathetic control of lung muscle found?
Postganglionic Nerve - M2
Airway smooth muscle - M2 and M3
How is muscle contraction controlled?
By stimulation of M3 receptors by Ach
What is the important feedback mechanism involved in parasympathetic control?
Ach feeds back to M2 receptors on the postganglionic nerve to stop further release of Ach
How are M3 receptors activated?
- Myosin light chain kinase helps with cross bridge formation for muscle contraction
- To stop contraction have to phosphorylate the myosin
How is lung muscle sympathetically controlled?
Activation of β2 adrenoreceptors on airway smooth muscle
- cAMP stimulates PKA
- PKA decreases myosin light chain kinase activity
- This leads to muscle relaxation
What can asthma sufferers be triggered by?
Atopic (extrinsic)
- Allergies, contact with inhaled allergens
Non-Atopic (intrinsic)
- Respiratory infections, cold air, stress, exercise, inhaled irritants, drugs
After a trigger how do asthma patient react?
Movement of inflammatory cells into the airways
Release of inflammatory mediators and subsequent bronchoconstriction
What are the characteristics of an asthma patient spirometry?
Decrease in FEV1 (forced expiratory volume in 1 min)
Decrease in FEV1% to below 80% of tidal volume
FVC unaltered
What is the link between M2 receptors and airway hypersensitivity?
Asthma is associated with an increase in parasympathetic activity
Shown as an increase in basal tone and increased muscle constriction in response to irritants
How is the link between M2 receptors and airway hypersensitivity shown in experiments?
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
What is the link between M2 receptors and asthma ?
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
What are the 3 main ways to treat asthma?
β2 Adrenergic agonists
Anticholinergics
Glucocorticoids
What are β2 Adrenergic agonists?
Short acting – Salbutamol
Longer acting – Salmeterol (delivered with corticosteroids)
What are anticholinergics?
Block the effects of endogenous Ach
Inhaled daily with actions via M1 and M3 receptors
E.g. Tiotropium bromide
What are glucocorticoids?
Anti-inflammatory actions
Inhaled steroids
E.g. Beclometasone
