K1. Smooth Muscle Physiology Notes

I. Smooth Muscle Anatomy
II. Smooth Muscle Electrophysiology
III. Contraction-Relaxation
IV. Smooth Muscle Control
V. Multi-Unit Smooth Muscle

Smooth muscle is layered and runs in several directions, enabling organs to change shape as different layers contract.

Actin and myosin form contractile units with structural differences from skeletal muscle.
Smooth muscle is not striated or arranged into sarcomeres, hence the term "smooth."
There is more actin and less myosin compared to skeletal muscle.
- Each myosin is surrounded by 12-15 actin molecules.
- The entire surface is covered in myosin heads.
- This arrangement allows for optimum overlap and tension, even when the smooth muscle stretches or expands.

Phasic Smooth Muscle: alternates between periodic contraction and relaxation cycles.
- Examples:
  - Esophagus (usually relaxed)
  - Intestine (cycles between contraction and relaxation)
Tonic Smooth Muscle: maintains some level of muscle tone.
- Examples:
  - Sphincter (relaxes to allow material to pass)
  - Vascular smooth muscle (contraction is varied as needed)

Myogenic action potentials originate in the muscle tissue.
- Slow wave potentials fire action potentials when they reach the threshold.
- Pacemaker potentials always depolarize to the threshold.
T-type $Ca^{2+}$ channels:
- Low-voltage-gated $Ca^{2+}$ channels
- Open at rest
- $Ca^{2+}$ influx through T-type channels produces slow depolarization until threshold.
At the threshold, L-type calcium channels open.
$Ca^{2+}$ influx leads to depolarization.
$K^+$ channels open.
$Ca^{2+}$ plateau: $Ca^{2+}$ influx is balanced out by $K^+$ efflux.
More $K^+$ channels open.
Repolarization occurs.

Single-Unit Smooth Muscle: "unitary smooth muscle"
- Most smooth muscle is single-unit, visceral smooth muscle, forming the walls of internal organs.
Structure: cells connected by gap junctions.
Function: coordinated control of large sheets of muscle.
Electrical signal at one cell spreads rapidly through the entire sheet of muscle.
- Along the sarcolemma
- Via gap junctions
- No t-tubules
Connected cells fire in sync with pacemaker cells.

The force of contraction is determined by the amount of $Ca^{2+}$ in the cytoplasm.
- Most $Ca^{2+}$ comes from the ECF.
- Some smooth muscle fibers have SR.
Calcium Handling
- Slow influx
- Slowly pumped out, resulting in contractions lasting seconds to minutes.

$Ca^{2+}$ enters via L-type $Ca^{2+}$ channels and/or SR.
$Ca^{2+}$ binds at calmodulin: calcium-dependent regulatory protein.
Activates myosin light chain kinase (MLCK): enzyme that phosphorylates myosin light protein chains.
Activates light myosin protein chains: small regulatory protein chains at the base of the myosin head.
Phosphorylated light chains have enhanced myosin ATPase activity.
Contraction occurs via the sliding filament model.
- Myosin ATPase is slow, leading to a slow increase in tension.
- Low ATP use results in slow fatigue.

$Ca^{2+}$ is cleared.
- SERCA pumps $Ca^{2+}$ into SR.
- $Ca^{2+}$ -ATPase pumps $Ca^{2+}$ into ECF.
- $Na^+-Ca^{2+}$ exchanger (NCX) pump $Ca^{2+}$ out of the cell and $3 Na^+$ in.
Myosin Light Chain Phosphatase (MLCP): enzyme that dephosphorylates myosin light chain.
- Dephosphorylated light chain leads to decreased myosin ATPase activity and contraction.
Reduced $Ca^{2+}$ - CaM complex results in reduced MLCK activity.

Contraction force is determined by MLCK activity and $Ca^{2+}$ sensitivity.
Force is proportional to MLCK activity.
- Dependent on $[Ca^{2+}]$ in the cytosol.
- High $[Ca^{2+}]$ leads to high MLCK activity, high myosin ATPase activity, high crossbridge formation, and more tension.
Calcium Sensitivity: responsiveness of myosin to $Ca^{2+}$ , dependent on the MLCK:MLCP ratio.
- High $Ca^{2+}$ + High MLCK:MLCP leads to high-force contraction.
- NT, hormones, and paracrine signals increase MLCP activity.
  - Low MLCK:MLCP results in lower force contraction.
  - Contraction desensitized to $Ca^{2+}$ is less effective at causing contraction.
- NT, hormones, and paracrine signals decrease MLCP activity.
  - Very high MLCK:MLCP leads to high force contraction.
  - Contraction sensitized to $Ca^{2+}$ is more effective at causing contraction.

Parasympathetic
- NT: Acetylcholine
- Receptor: m3AChR
- Contraction: bronchoconstriction, digestion, secretion, pupil constriction
Sympathetic Nervous System
- NT: Norepinephrine; Hormone: Epinephrine
- Receptors:
  - $α1$ → Gq → contraction (vasoconstriction, pupil dilation)
  - $β2$ → Gs → relaxation (vasodilation, bronchodilation)
ANS and hormonal signaling may trigger
- $Ca^{2+}$ release from SR
- Phosphorylation of $Ca^{2+}$ or $K^+$ channels
- Phosphorylation of MLCK or MLCP