Respiration III Flashcards
What controls the diameter of the lumen of the airways?
What is this dependant on?
Airway smooth muscle
Dependant on GPCR cascades that make the muscle contract/relax
How is the overall relaxation/contraction state of the airway smooth muscle determined?
By the OVERALL activation fo the 3 GPCR cascades:
- Gq
- Gs
- Gi
What are the receptors of the Gq pathway?
- M3 muscarinic
- H1 histamine
- BK bradykinin
What is the Gq pathway linked to?
Airway CONSTRICTION
What is the Gq pathway that stimulates airway CONTRACTION?
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
What are the receptors that activate the Gs pathway?
- Beta2 adrenergic receptors
- VIP receptors
What is stimulation of the Gs pathway linked to?
Airway RELAXATION
What is the Gs pathway that stimulates airway RELAXATION?
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
As well as activating adenylate cyclase, what else does Gs do?
What does this lead to?
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
What are the receptors acting through the Gi pathway?
M2 muscarinic receptors
What does the Gi pathway lead to?
What does this cause?
INHIBITION of ADENYLATE CYCLASE
- Counteracts the stimulatory effect of Gs activation (normally relaxes the airways)
- OPPOSES smooth muscle relaxation
As well as inhibiting adenylate cyclase, what else does Gi do?
What does this lead to?
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
What are the 3 controls of of the airway smooth muscle?
1) Sympathetic nervous system
2) Parasympathetic nervous system
3) Humoral factors
How does the sympathetic nervous system control the smooth muscle of the airways?
Release of NOREPINEPHRINE
Leads to DILATION
How does the parasympathetic nervous system control the smooth muscle of the airways?
Release of acetylcholine from the VAGUS NERVE
Leads to CONSTRICTION
What receptors does Ach from the vagus nerve act on?
Muscarinic receptors
What HUMORAL factors control the smooth muscle of the nervous system?
1) Epinephrine - leads to DILATION
2) Histamine - leads to CONSTRICTION
When is histamine released?
During inflammatory responses
How does histamine lead to constriction?
- Activation of the H1 receptor
- Activates the Gq pathway
Where are the receptors involved in parasympathetic control present?
Which receptors control smooth muscle contraction?
1) Postganglion neurons
- M2 receptors
2) Airway smooth muscle (target)
- M2 and M3 receptors
M3 receptors control smooth muscle contraction
What is the negative feedback in the control of smooth muscle contraction in parasympathetic control?
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
What happens if the feedback mechanism in the parasympathetic control of smooth muscle is disrupted?
Leads to ASTHMA and HYPERSENSITIVE airways
What happens when the M3 receptors are activated through parasympathetic control?
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
What happens at the same time as the Gq pathway in smooth muscle contraction in the airways?
Protein kinase C (PKC) phosphylates and INHIBITS myosin light chain PHOSPHATASE
–> PREVENTING relaxation of the muscle
How is contraction of the airway smooth muscle stopped?
By allowing activation of MLCP - can remove the phosphate from the myosin chain and prevent cross-bridge formation
What is a beta2 adrenoreceptor agonist?
What happens when it binds to B2 adrenoreceptors?
Salbutamol
When bind:
- Activate the receptor
- Activate the Gs pathway
- Activating PKA (through activation of adenylate cyclase and cAMP)
What does PKA phosphorylate to induce smooth muscle relaxation?
What does this cause?
Phosphorylates MLCK at a DIFFERENT SITE to PKC
Causes a REDUCTION in the activity of MLCK
What does the reduction of Ca2+ inside the cell (through the activation of BK K+ channels in muscle relaxation) cause?
- Turns off Ca2+/CaM signalling
- Inactivates MLCK
At the same time as the activation of B2 adrenoreceptors by the SNS to increase muscle relaxation, what also occurs?
What does this cause
1) Activation of BK K+ channels
2) Stimulation of MLCP
- Dephosphorylation of myosin light chain
- Loss of cross linking
What is asthma caused by?
Hypersensitive airways
Due to the increase in parasympathetic activity and M2 receptors
What are the 2 triggers for asthma?
1) Atopic (extrinsic)
2) Non-atopic (intrinsic)
What are the atopic triggers of asthma?
Allergens/allergies
What are the non-atopic triggers of asthma?
- Respiratory infections
- Stress
- Cold air
- Exercise
- Inhaled irritants
What is the response in asthma?
1) Movement of inflammatory cells into the airways
2) Release of inflammatory mediators
3) BronchoCONSTRICTION
What are the inflammatory mediators released from inflammatory cells during asthma?
Histamine
Describe the spirometry in asthma
- 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)
How are hypersensitive airways caused?
- Inhibition of the negative feedback of Ach on the M2 receptors
- More Ach released
- Hypersensitivity
What does hypersensitivity affect the muscles of the airways?
Increases BASAL TONE
Increases MUSCLE CONSTRICTION in response to irritants
In the antigen-challenge, what is the change in M2 function linked to?
How?
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
What does ozone exposure cause?
Activation of the eosinophil pathway:
- Synthesis of MBP
- Inhibition of receptors
What does virus exposure cause the activation of?
- Macrophages
- Neuraminidase
- Interferons
What does the activation of neuraminidase cause?
Cleavage of part of the M2 receptor and changes to the binding affinity for Ach
What does the activation of interferons cause?
Reduced M2 gene expression
How are cases of asthma REDUCED in diabetics?
Insulin reduces M2 receptors
Reduced insulin in diabetics
What are 3 treatments for asthma?
1) Beta2 adrenergic agonists
2) Anticholinergics
3) Glucocorticoids
What do Beta2 adrenal agonists do?
Acitvate the Gs pathway
What are the shorter acting Beta2 adrenal agonists?
Salbutamol
What are the longer acting Beta2 adrenal agonists?
What must this be delivered with?
Salmeterol
Delivered with corticosteroids
What do anticholinergics do?
- BLOCK the effects of Ach on the M3 receptor
- Preventing activation of the Gq pathway
- Causing airway relaxation
What do glucocorticoids do?
Anti-inflammatory:
- Prevent the binding of eosinophils to the nerve terminals
- Upregulate anti-inflammatory genes
- Inhibit inflammatory genes
