HSC Pulse Memorize

Vascular smooth muscle (VSM) contraction

VSM has slow, sustained (tonic) contractions, while cardiac muscle contracts rapidly and briefly.

Key regulatory protein missing in VSM

Troponin

Arrangement of actin and myosin in VSM

Not in striated bands, but still highly organized to allow tonic contraction and lumen diameter control.

Types of stimuli triggering VSM contraction

Mechanical (stretch), electrical (depolarization), and chemical (ligand-receptor signaling).

VSM contraction in response to passive stretch

Myogenic response

Calcium channels opening during VSM depolarization

L-type voltage-dependent calcium channels

Chemicals that can trigger VSM contraction

Norepinephrine, angiotensin II, vasopressin, endothelin-1, thromboxane A2

Mechanism of contraction in VSM due to increased intracellular Ca²⁺

Ca²⁺ binds to calmodulin → activates MLCK → phosphorylates myosin light chains (MLC) → cross-bridge formation with actin

Protein Ca²⁺ binds to during VSM contraction

Calmodulin

Activation by Ca²⁺-calmodulin complex

Myosin light chain kinase (MLCK)

Effect of MLCK phosphorylating myosin light chains

Myosin can bind to actin → contraction occurs

Ways VSM relaxation can happen

1) Decreased Ca²⁺ levels, 2) Increased cAMP inhibits MLCK, 3) MLCP dephosphorylates MLC

Enzyme removing phosphate from myosin light chains

Myosin light chain phosphatase (MLCP)

Determining factor for VSM contraction or vascular tone

The balance between MLCK and MLCP activity (phosphorylation state of MLC)

Effect of Gq protein activation in VSM

Increases IP₃ → Ca²⁺ release from SR and activates Rho-kinase → inhibits MLCP → contraction

Ligands activating Gq pathways in VSM

Norepinephrine (α₁), angiotensin II (AT₁), vasopressin (V₁), endothelin-1 (ETₐ), acetylcholine (M₃)

Effect of Gs protein activation in VSM

Increases cAMP → inhibits MLCK → relaxation

Ligands activating Gs pathways in VSM

Epinephrine (β₂), prostacyclin (IP), adenosine (A₂)

Effect of Gi protein activation in VSM

Decreases cAMP → enhances MLCK activity → contraction

Factors controlling intracellular Ca²⁺ concentration in VSM

1) Ca²⁺ influx, 2) Ca²⁺ release from SR, 3) Ca²⁺ removal from cytoplasm

Mechanism of Ca²⁺ re-sequestration into the sarcoplasmic reticulum

By an ATP-dependent calcium pump

Mechanism of Ca²⁺ removal from the cell

Through an ATP-dependent pump or sodium-calcium exchanger (NCX)

Final result of increased MLC phosphorylation in VSM

Increased contraction

Final result of decreased MLC phosphorylation in VSM

Relaxation

What type of muscle is smooth muscle?

Non-striated, involuntary muscle found in walls of organs and tubes (e.g., blood vessels, bladder, uterus).

What initiates contraction in smooth muscle?

Calcium (Ca²⁺) binding to calmodulin, which activates myosin light chain kinase (MLCK).

How does MLCK activate contraction?

It phosphorylates the 20-kDa light chain of myosin, allowing actin-myosin cross-bridge cycling.

What provides energy for smooth muscle contraction?

Myosin ATPase activity, which hydrolyzes ATP during cross-bridge cycling.

What is smooth muscle tone?

Low-level MLC phosphorylation and contraction in the absence of external stimuli.

How does calcium enter smooth muscle cells?

Through receptor-operated and voltage-operated (L-type) calcium channels.

What intracellular organelle stores Ca²⁺?

Sarcoplasmic reticulum (SR)

What are the two key second messengers in smooth muscle contraction?

IP₃ and DAG (produced by phospholipase C activation)

What does IP₃ do in smooth muscle cells?

Binds SR receptors to release Ca²⁺ into the cytosol.

What does DAG do in smooth muscle cells?

Activates protein kinase C (PKC), which promotes contraction by phosphorylating target proteins.

What is the role of PKC in smooth muscle contraction?

Phosphorylates proteins like Ca²⁺ channels and others that enhance contraction.

What receptor pathway initiates Ca²⁺ sensitization?

RhoA/Rho kinase pathway

What does Rho kinase do in smooth muscle?

Inhibits myosin light chain phosphatase (MLCP) by phosphorylating its myosin-binding subunit.

What is the effect of Rho kinase activation?

Maintains MLC phosphorylation, sustaining contraction (Ca²⁺ sensitization).

What is the role of RhoGEFs in smooth muscle signaling?

They activate RhoA after receptor stimulation (e.g., PDZ-RhoGEF, LARG, p115-RhoGEF).

What drugs inhibit Rho kinase?

Fasudil and Y-27632

What is the result of Rho kinase inhibition?

Relaxation of smooth muscle and reduced blood pressure.

What is the role of CPI-17 in contraction?

Inhibits MLCP (downstream of PKC), promoting contraction.

What is telokin's role in smooth muscle?

Stimulates MLCP in phasic smooth muscle to promote relaxation.

What enzyme decreases MLCK sensitivity to Ca²⁺?

Calmodulin-dependent protein kinase II (promotes relaxation).

What two actions are required for smooth muscle relaxation?

1) Decrease in intracellular Ca²⁺, 2) Increased MLCP activity

How is Ca²⁺ removed from the cytosol during relaxation?

By SR Ca²⁺-ATPase (SERCA) and plasma membrane Ca²⁺ pumps (Ca,Mg-ATPase), and Na⁺/Ca²⁺ exchangers.

What SR proteins help bind and store Ca²⁺ during relaxation?

Calsequestrin and calreticulin

What stimulates the plasma membrane Ca²⁺ pump?

Binding of calmodulin to its autoinhibitory domain.

What drugs block Ca²⁺ reuptake into the SR?

Vanadate, thapsigargin, and cyclopiazonic acid

What blocks plasma membrane Ca²⁺ entry during relaxation?

Calcium channel blockers (e.g., dihydropyridines, phenylalkylamines, benzothiazepines)

What is the Na⁺/Ca²⁺ exchanger?

A low-affinity antiporter on the plasma membrane that removes intracellular Ca²⁺

What are some causes of abnormal smooth muscle contraction?

Altered Ca²⁺ handling, MLC phosphorylation, receptor number/affinity, and Rho kinase activity.

How does Rho kinase overactivity affect disease?

Contributes to hypertension, erectile dysfunction, asthma, and atherosclerosis.

How does impaired NO or cGMP signaling affect smooth muscle?

Reduces relaxation response, contributing to vascular dysfunction.

What is the final step required to initiate relaxation?

Decreased Ca²⁺ and activation of MLC phosphatase to dephosphorylate myosin.