Lecture 22: Cellular Physiology of Muscle - Smooth

How many synaptic contacts does each autonomic nervous system neuron make with a smooth muscle cell?

multiple contacts

What do varicosities contain?

presynaptic machinery

What are varicosities close to?

postsynaptic membrane of smooth muscle cell

Characterize multiunit smooth muscle.

• each cell receives synaptic input

• few gap junctions between cells

• each cell can contact independently of its neighbor

• fine control

What are examples of multiunit smooth muscle.

• iris and ciliary body of the eye

• piloerector muscles of the skin

Characterize unitary smooth muscle.

• group of cells that work as syncytium

• gap-junction coupled

• Ca2+ waves spread among coupled cells

What are examples of unitary smooth muscle?

• walls of visceral organs

• blood vessels

True or False: APs don’t occur in some types of multiunit smooth muscle.

true

What is junctional potential similar to?

EPP

What triggers a junctional potential?

release of ACh from autonomic neurons

Briefly describe the junctional potential spread.

graded, spread electronically

What do junctional potentials trigger?

the opening of L-type Ca2+ channels and Ca2+ entry

Contraction can also happen in some cells in response to what? What specifically?

GPCR activation, PLC → IP3 → Ca2+ release from SR

What does prolonged entry of Ca2+ during plateau lead to?

prolonged contraction

What does regular, repetitive oscillations in V_m lead to?

repetitive contractions

What is occurring during the depolarizing phase of smooth muscle APs?

opening of L-type Ca2+ channels

Compare the rate of AP rise in smooth and skeletal muscles.

slower rate of rise than APs in skeletal muscle

Smooth muscle APs have slow repolarization. What channels are causing this?

delayed activation of voltage-gated K+ channels or Ca2+-activated K+ channels

List the steps for the generation of slow waves in smooth muscle.

1. voltage-gated Ca2+ channels open

2. AP spike

3. Ca2+ influx, rise in internal Ca2+ concentration

4. open Ca2+-dependent K+ channels

5. slow hyperpolarization

6. voltage-gated Ca2+ channels close and internal Ca2+ concentration decreases

7. Ca2+-dependent K+ channels close

What are the 3 major pathways for driving an increase in intracellular Ca2+ concentration in smooth muscle?

• Ca2+ entry via L-type Ca2+ channels

• Ca2+ release from SR via RYR or IP3R

• Ca2+ entry via voltage-independent/store-operated channels

What triggers the opening of L-type voltage-gated Ca2+ channels?

both graded depolarizations and APs

Where is Ca2+ released from?

the SR

True or False: In smooth muscle (but not skeletal), increased intracellular Ca2+ concentration stimulates Ca2+-activated K+ and Cl- channels.

true

What are the 2 mechanisms for Ca2+ release from the SR?

• Ca2+ entry via L-type Ca2+ channels activates RYRs on SR (CICR)

• IP3 activation of IP3 receptor on SR (downstream of GPCR activation) [especially important for smooth muscle]

Ca2+ sparks can also occur spontaneously via random what?

random RYR opening

What does SOCE stand for?

store-operated Ca2+ entry

What happens when SR Ca2+ is depleted?

• STIM aggregates in regions of SR membrane close to the plasma membrane

• triggers direct interactions between STIM and Orai tetramers on plasma membrane

• Orai tetramers aggregate to form Ca2+ channel → Ca2+ entry

What happens when SR Ca2+ rises?

STIM aggregation is suppressed and SOCE is halted

What is STIM?

a Ca2+-sensing protein

Which cells don’t have CaV channels?

• secretory epithelial

• mast cells

• lymphocytes

Are SR Ca2+ release and SOCE voltage-dependent or voltage-independent?

voltage-independent

What are the forms of pharmacomechanical coupling?

intracellular Ca2+ elevation initiated by chemical activators rather than Vm changes

True or False: Drugs can affect smooth muscle contraction by modulating pharmacomechanical coupling and independent of AP generation.

true

List the process of how cross-bridge cycling is initiated in smooth muscle.

1. increase in intracellular Ca2+ concentration

2. Ca2+ ions bind to CaM

3. Ca2+-CaM complex activities activate myosin light chain kinase (MLCK)

4. MLCK phosphorylates regulatory myosin light chains (MLC) on myosin neck

5. conformational change of myosin head increases ATPase activity

6. myosin can then interact with actin and be a molecular motor

Contraction cannot begin until what? Is this a fast or slow process?

MLCK increases ATPase activity of myosin; slow process

What terminates smooth muscle contraction?

myosin light chain phosphatase (MLCP)

What does MLCP do?

dephosphorylates MLCs on the neck region

What can Ca2+-independent contractions result from?

• increase in rate of MLC phosphorylation by MLCK

• decrease in rate of MLC dephosphorylation by MLCP

What decreases MLCP activity?

protein kinase C (PKC)

True or False: Some stimuli generate contraction via PKC-mediated decreases in MLCP activity.

true

What does larger MLC phosphorylation and smaller MLC dephosphorylation lead to?

sustained contractions and increased contractile force

What does decreased MLC phosphorylation and increased MLC dephosphorylation lead to?

increased threshold for contractile activation

What is MLC phosphorylation regulated by?

• Ca2+-CaM complex

• intracellular Ca2+ concentration

What is MLC dephosphorylation regulated by?

• Ca2+ sensitivity of MLCK

• inhibition of MLCP

What phosphorylates MLCK?

• PKA

• PKC
  CaMK

What does decreased MLCK sensitivity lead to?

Ca2+-CaM activation

Review the following chart.