smooth muscle function

Question 1

How smooth muscles contract

Answer 1

Myosin slides ober actin filaments to shorten the muscle. Initiated by increasing IC [Ca].

Mechanism: Calcium-bound calmodulin activates myosin light chain kinase (MLCK), which can then use ATP to phosphorylate myosin.

The phosphorylation of myosin is reversed by myosin light chain phosphatase (MYPT1).

Question 2

Initiation of smooth muscle contraction by different channels/receptors

Answer 2

GqPCRs, LGICs, and VGCCs to increase IC calcium, contracting the muscle

Gq: generation of IP3, which binds to receptors on the ER, which release IC stores of Ca

LGICs: ATP activation of P2X1 allows influx of Na and Ca, while effluxing K+.

VGCCs: following partial depolarisation, L-type VGCCs open, with Ca influx through it.

Question 3

what causes Sustained SM contraction in Gq-mediated contraction

Answer 3

With Gq-mediated SM contraction, removal of calcium does not stop the contraction.

The Gq also activates PKC, which phosphorylates MYPT1, preventing the dephosphorylation of phosphomyosin.

Question 4

Signalling pathways to promote SM relaxation

Answer 4

K+ channels, which hyper polarise the plasma membrane, reducing VGCC influx.

Elevating cGMP by activation of RGC or soluble guanylyl cyclase, which activates PKG, which activates hsp20 to inhibit actin and myosin binding.

Elevating cAMP (GsPCR-mediated), which activates PKA to phosphorylate MLCK, preventing the phosphorylation of myosin necessary in SM contraction.

Question 5

receptors that mediate Vascular SM contraction

Answer 5

Sympathetic innervation by NA (a1-ARs) to increase [Ca] and PKC activity, and by ATP (P2X1) to increase [Ca].

Hormonal and platelet-derived ligands can also act at receptors in lumen of blood vessels.

Adrenaline (a1-AR), angiotensin II (AT1), endothelia-1 (ETA), and platelet derived thromboxane A2 (TP prostanoid receptor) all cause contraction by increasing [Ca] and PKC activity.

Question 6

receptors that mediate Vascular SM relaxation

Answer 6

Endothelial vascular SM relaxed by endothelin-1 (ETB), thromboxane A2 (TP prostanoid receptor) and thrombin (PAR1) all by increasing NO, PGI2 and EDHF.

B2-ARs (NA), A2A (adenosine as agonist), and IP prostanoid (prostaglandin I2) receptors all found in smooth muscle, and increase cAMP

RGC-C (ANP as agonist), soluble guanylyl cyclase (NO activated) increase cGMP

Question 7

Pharmacological targeting to inhibiting vascular SM contraction

Answer 7

AT1 antagonists (losartan), ACEIs (captopril), and L-type VGCC inhibitors (nifedipine) are used to inhibit SM contraction.

soluble gunaylyl cyclase agonists (glyceryl trinitrate), PDE5 inhibitors (sildenafil), and KATP activators (diazoxide) enhance the SM relaxation

Question 8

receptors that mediate tone of Intestinal and bladder SM

Answer 8

Bowel motility mediated by Gq-coupled mAChR (enhances contraction)

NA impinging on parasympathetic nerves act on a2-ARs (Gi) to reduce ACh release, and B3-ARs (Gs) to increase cAMP. Mediate relaxation.

Question 9

Examples and mechanisms of Pharmacological exploitation of intestinal/bladder SM

Answer 9

M3 antagonists and mu-opioid agonists used to inhibit contraction for treating diarrhoea.

Papaverine (PDE inhibitor) inhibits cyclic nucleotide hydrolysis (e.g., cAMP and cGMP) to enhance SM relaxation.

M3 antagonists (oxybutynin) and B3-AR agonists (mirabegron)used to reduce bladder tone to treat overactive bladder.

M3 agonists used to promote SM contraction to treat urinary retention.

Question 10

receptors that mediate Bronchial SM tone

Answer 10

M3 receptors: increase Ca2+, PKC - bronchconstriction

Systematic adrenaline activates B2-AR to increase cAMP - bronchodilatation

Question 11

Pharmacological exploitation of bronchial SM innervation

Answer 11

Aclindium (M3 antagonist) and montelukast (CysLT1 antagonist) to prevent SM constrction

Salbutamol (B2-AR agonist) and roflumilast (PDE4 inhibitor) to increase SM relaxation