Learning Objective
By the end of this section, you should be able to explain the molecular mechanisms that regulate smooth muscle contraction and relaxation, including the roles of calcium, calmodulin, MLCK, and MLC phosphatase, and how signaling pathways modulate cytosolic calcium to control smooth muscle tone.
Regulation of Smooth Muscle
Calcium Entry and Release
- Smooth muscle contraction is initiated by an increase in cytosolic calcium.
- Voltage-gated L-type calcium channels in the sarcolemma open in response to depolarization, allowing calcium influx into the cytosol.
- This calcium influx can trigger further calcium release from the sarcoplasmic reticulum (SR) via calcium-induced calcium release, similar to cardiac muscle.
- IP3-mediated calcium release occurs when an agonist (e.g., norepinephrine binding α₁-adrenergic Gq-coupled receptors) stimulates phospholipase C, generating IP3. IP3 binds SR receptors, causing additional calcium efflux.
Calcium-Calmodulin Activation of MLCK
- Cytosolic calcium binds calmodulin (CAM) to form the calcium-calmodulin complex.
- This complex activates myosin light chain kinase (MLCK), which phosphorylates the myosin light chain (MLC).
- Phosphorylated MLC increases myosin’s affinity for actin, resulting in smooth muscle contraction.
Cross-Bridge Cycling
- Similar to striated muscle, ATP is required to dissociate actin from myosin.
- If MLC remains phosphorylated, myosin rebinds actin, producing sustained tension.
- Unlike striated muscle, smooth muscle can maintain tonic contraction with lower energy expenditure through this “latch state.”
Relaxation Mechanism
- MLC phosphatase dephosphorylates MLC, decreasing myosin’s affinity for actin and causing smooth muscle relaxation.
- The balance between contraction and relaxation depends on cytosolic calcium:
- High calcium → MLCK dominates → contraction
- Low calcium → MLC phosphatase dominates → relaxation
- Calcium Clearance
- Smooth muscle reduces cytosolic calcium via mechanisms similar to cardiac cells, including Ca²⁺ pumps in the SR and plasma membrane and Na⁺/Ca²⁺ exchangers, to restore basal tone.
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