Smooth Muscle

Question 1

Smooth Muscle

Answer 1

• more variable than skeletal
• must operate over a range of lengths
• layers run in several direction - contract and relax much more slowly
• use less energy to generate and maintain force
• can sustain contraction without fatigue
• contraction initiated electrically or chemically
• controlled by autonomic nervous system
• Ca2+ from Extracellular space and/or SR
• Ca2+ initiates cascade eventually turning on myosin ATPase

Question 2

Properties of Smooth Muscle

Answer 2

• spindle-shaped, uninucleate cells
• NO troponin and T-tubules
• intermediate filaments (non-contractile) and dense bodies (similar to z-lines) form extensive cytoskeletal structure
• thin filaments are anchored to the cell membrane or dense bodies

Question 3

Smooth Muscle Caterogies

Answer 3

1. Location
2. Contraction Pattern
3. Communication with neighbouring cells
   
   • unitary and multiunit

Question 4

Location of Smooth Muscle

Answer 4

1. Vascular: blood vessel walls
2. Gastrointestinal: walls of digestive tract and associated organs
3. Urinary: wall of bladder and ureters
4. Respiratory: airway passages
5. Reproductive: uterus in females and other structures
6. Ocular: iris and ciliary body

Question 5

Contraction Pattern

Answer 5

1. Phasic smooth muscle that is usually relaxed (esophagus)
2. Phasic smooth muscle that cycles between contraction and relaxation (intestine)
3. Tonic smooth muscle usually contracted (sphincter)
4. Tonic smooth muscle who contraction is varied as needed (vascular smooth muscle)

Question 6

Unitary Smooth Muscle

Answer 6

• single unit
• contains gap junction similar to cardiac muscle cell
• allows coordination of many cells causing muscle to contract as a single unit
• referred to as Visceral Smooth Muscle

Question 7

Multiunit Smooth Muscle

Answer 7

• not electrically coupled
• behave on their own, not as a unified unit
• iris and ciliary body of eye, in the male reproductive tract and in uterus except prior to delivery

Question 8

Smooth Muscle Contract Because…

Answer 8

• response to synaptic transmission or electrical coupling
• innervated by the autonomic nervous system
• can be innervated by multiple neurons, capable of releasing different neurotransmitters

Question 9

Different Receptor Subtypes in Smooth Muscle

Answer 9

1. alpha-adrenergic: Gi vessel constriction

2. beta-adrenergic: airway dilation

Question 10

Alterations of Smooth Muscle Tension

Answer 10

• circulating hormones, stretch and local factors

- paracrine signals, acidity, oxygen and carbon dioxide concentration, and osmolarity

Question 11

Action Potentials of Smooth Muscles

Answer 11

• can be initiated by neural, hormonal, or mechanical stimulation
• upstroke slower because Ca2+ channels propagate the AP instead of Na+
• repolarization slower because Ca2+ channels inactivate slowly and there is a delayed activation of voltage gated k+ and in some cases Ca2+-activated K+ channels
• happen only in unitary muscle

Question 12

Slow Wave Potentials in Smooth Muscle

Answer 12

• fire action potentials when they reach threshold

- slowly increase to threshold

Question 13

Pacemaker Potential

Answer 13

• always depolarize to threshold

Question 14

Contraction without Action Potentials

Answer 14

• smooth muscle cells produce a wide range of membrane potentials and in some smooth muscle Vm oscillations can lead to tonic contractions in the absence of APs
• APs don’t usually occur in multiunit smooth muscle
• autonomic neurons create a local depolarization that spreads electrontonically (graded fashion) throughout muscle fibre triggering Ca2+ entry

Question 15

Electrical Activity in Single Unit Smooth Muscle

Answer 15

• Autonomic AP initiation
  
  • spikes and plateaus
• Spontaneous AP
  
  • slow wave
  • pacemaker

Question 16

Electrical Activity in Multiunit Smooth Muscle

Answer 16

• graded potentials

- contraction due to electrical signalling known as electromechanical coupling

Question 17

Ca2+ Activated Contraction

Answer 17

• release increased by 3 ways:
  1. Ca2+ entry through voltage gated channels or ligand gated ion channels
  2. Ca2+ release from SR
  
  • Ca2+ induced Ca2+ release from RyR
  • IP3 Ca2+ release from IP3R
    3. Ca2+ entry through voltage-indepentdent channels
  • store operated Ca2+ channels
  • stretch activated channels

Question 18

Ca2+ Entry through Voltage-Gated Channels

Answer 18

• smooth muscle cells respond to graded stimulation or action potentials
• both produce an influx of Ca2+ through voltage-gated L-type Ca2+ channels

Question 19

Ca2+ Release from SR

Answer 19

• less SR than in skeletal and cardiac muscle
• occurs via Ca2+-induced Ca2+ release and IP3 pathway
• IP3 pathway can because contraction with minimal depolarization and negligible extracellular Ca2+ influx

Question 20

GPCR-phospholipase C Signal Transduction (alpha-adrenergic receptor)

Answer 20

1. signal molecule activates receptor and associated G protein
2. G protein activates phospholipase C (PLC) , an amplifier enzyme
3. PLC converts membrane phospholipids into diacylglycerol (DAG), which remains in the membrane, and IP3, which diffuses into the cytoplasm
4. DAG activates protein kinase C (PKC), which phosphorylates proteins
5. IP3 causes release of Ca2+ from organelles, creating a Ca2+ signal

Question 21

Ca2+ Entry through Voltage-Independent Channels

Answer 21

• depletion of Ca2+ in SR causes activation of store-operated channels
• causes a Ca2+ influx across the cell membrane
• [Ca2+]i allowed to remain elevated and replenish SR
• STIM1 on SR
• Orai-1 proteins make up CA2+ channel on cell membrane

Question 22

Pharmacomechanical Coupling

Answer 22

• Ca2+ release from SR via IP3 pathway (IP3 binds to IP3 receptor)
• entry of Ca2+ via store operated channels are voltage independent and
• ex) drugs, excitatory neurotransmitters and hormones can induce smooth muscle contraction with no AP generation
• occurs when chemical signals change muscle tension through signal transduction pathways with little or no change in Vm

Question 23

Stretched Activated Contraction

Answer 23

• stretched activated ion channels in the cell membrane that lead to depolarization when activated
• Ca2+, Cl-, TRPV4, TRPC1, TRPC6
• cause an internal of Ca2+ from SR through RyR
• shown to cause phosphorylation of myosin light chain leading to contraction

Question 24

Calmodulin

Answer 24

• Ca2+ binding protein (like troponin)
• Ca2+ signal in smooth muscle
• 4 Ca2+ ions bind to calmodulin

Question 25

Initiating Cross Bridge Cycle in Smooth Muscle

Answer 25

• Ca2+ calmodulin complex activates enzyme MLCK
• MLCK phosphorylates the regulatory light chain near myosin head altering conformation and increase ATPase activity and allows it to interact with actin
• activates the thick filaments (caldesmon and calponin)

Question 26

Increasing Force Generated

Answer 26

increase Ca2+ entry > increased MLCK activated > more myosin heads activated > increased force generated

Question 27

Initiation of Cross Bridge Cycle in Smooth Muscle

Answer 27

1. intracellular CA2+ concentration increase when Ca2+ enters cells and released by SR
2. Ca2+ binds to calmodulin (CaM)
3. Ca2+-calmodulin activates MLCK
4. MLCK phosphorylates light chains in myosin heads and increases myosin ATPase activity
5. active myosin crossbridges slide along actin and create muscle tension

Question 28

Cross Bridge Cycle in Smooth Muscle

Answer 28

• occurs slower

Question 29

Relaxation of Smooth Muscle

Answer 29

• Ca2+ moves back to SR and extracellular space
• Ca2+ removal does not immediately lead to relaxation
• regulatory light chain must be dephosphorylated by MLCP
• even after dephosphorylation some smooth muscle can maintain force for an extended period of time with little AP (Latch state)

Question 30

Ca2+ Sensitivity

Answer 30

• neurotransmitters, hormones and paracrine molecules alter Ca2+ sensitivity by modulating MLCP
• changes in phosphatase activity alter myosin’s response to Ca2+

Question 31

Increasing Contractile Force

Answer 31

• largely depends on the balance of MLC phosphorylation and dephosphorylation
• MLC phosphorylation is regulated by the Ca2+-CaM complex, which in turn depends on levels of intracellular Ca2+
• Contractile control by regulating Ca2+ sensitivity of proteins regulating contraction
  
  • Inhibiting MLCP or activating MLCK leading to greater contraction at lower [Ca2+]i