8. Smooth Muscle Histology and Physiology Flashcards
• Locations: – Wall of \_\_\_\_ organs, blood vessels, \_\_\_\_ of the eye, \_\_\_\_ muscle of the hair follicles. • Regulation of the internal environment: e.g. movement of fluids, air. • Capable of \_\_\_\_ and \_\_\_\_. • Very economical in energy terms. • Involuntary control: – \_\_\_\_ system. – Circulating \_\_\_\_. – \_\_\_\_ hormones.
• Multiple arrangements:
– ____
– ____
– ____
tubular
iris and ciliary body
piloerector
contraction
relaxation
autonomous
hormones
local
sheets
rings
bundles
III. Smooth Muscle
Unique to smooth: capable of contraction and relaxation; striated muscle is always referred to by contraction, only relaxes once stimulation is eliminated; smooth muscle has ____ (neural/hormonal) that induce a contraction (similar to skeletal muscle), and there are modulators that induce ____
Steady state of smooth muscle = always ____ (mechanisms to induce relaxation smooth muscle, different from skeletal)
Smooth muscle uses little energy when compared to skeletal muscle (binding actin to myosin, and myosin in smooth muscle has a low rate of ATPase-activity [____ lower]) > contraction is much ____ than skeletal, but very ____
regulators
relaxation
contracted
100-fold
slower
cheap
Smooth Muscle Histology
• The smooth muscle cell: • Small: average length = \_\_\_\_ μm. • Fusiform with a \_\_\_\_ nucleus. • not \_\_\_\_. • \_\_\_\_ instead of Z disks. • Ionic connections between cells through gap junctions: \_\_\_\_.
Cell that is nothing like skeletal/striated muscle > these cells can be confused with connective tissue cells = ____; similar phenotype: small (similar to euk cell in mammals)
Cytoplasm has no indication of ____
Highly interconnected (both mechanical and electrical connections) > induced to contract and relax as a single functional unit, in a coordinated manner
Each cell has one nucleus, but the ____ acts sintitially (due to the nature of their mechincal/electrical connections)
50-500 single central striatied dense bodies functional syncytium
fibroblasts
sarcomeres
organ
The Smooth Muscle Cell
- No ____ system.
- Instead of T tubules → ____:
- Invaginations of the sarcolemma:
- ↑ ____ → ↑ Ca2+ transport.
- Associated with the ____.
- Sarcoplasmic reticulum:
- Poorly ____.
- Organized in tubes or sheets.
- Myofilaments:
- Thick ____ (slow myosin) filaments.
- Thin ____ filaments.
- Intermediate filaments (desmin, vimentin).
- Cytoplasmic and plasma membrane dense bodies (α-actinin):
- Functionally similar to ____.
- Attachment of actin and intermediate filaments.
- Cell connections:
- Mechanical: through ____
- Electrical: through gap junctions - ____.
- ____ surrounding each SMC.
T tubules
caveolae
surface area
SR
developed
myosin
actin
Z disks
desmosomes
funtional syncytium
basal lamina
The Smooth Muscle Cell
No sarcomeres
Caveolae > increase ____ > enrichment in receptors involved with modulation, and in calcium channels
SR in smooth is morphologically identical to a ____ (like in fibroblasts)
Myofilaments are not bound to Z-disks > dense bodies (two types): ____ dense bodies, and ____ dense bodies > built by same protein as Z disk, but structure is very different
Electrical connection > flow of ions, ions traffick from one cell to the next thereby transmitting the contractile impulse
Mechanical connection > ensures that cells that are tightly attached will be pushed/pulled > ____ of smooth muscle fiber
____ is produced by smooth muscle cell
SA
regular ER
PM
cytoplasmic
coordinated
basal lamina
Smooth Muscle Histology
Longitudinal > ____ nuclei
Cross > the tissue is not different from connective tissue in what they produce [???] (elastin, etc.) but can uniquely be stimulated
centrally located
Structural Arrangements of SM Fibers: Circular Organization
- Typical of ____ and ____.
- Partially contracted at all times: ____.
- Vasoconstriction: additional contraction, which ____ the diameter of the vessel lumen.
- Vasodilation: relaxation, which ____ the diameter of the vessel lumen.
Circular organization > BV and airways > muscle cells are partially contracted at all times, the vessel is never completely relaxed > the ____: partially contracted, or muscle tone/tonicity
From this basal state > BV can be induced to contract > vasoconstriction > modulators increase contraction and diameter is reduced
Other modulators that induce vasodilation, opening the lumen of vessel/airway by relaxing the SMC
BV
airways
muscle tone
narrows
widens
steady state
Structural Arrangements of SM Fibers: Circular and Longitudinal Organization
• Typical of GI tract organs: e.g. ____ and ____ intestines.
- Two layers:
- Outer: ____.
- SM fibers run parallel to organ’s long axis.
- Contraction: organ ____.
• Inner: ____.
• SM fibers run around circumference of
organ.
• Contraction: organ ____
• Both layers coordinate contractions and relaxations: ____ movements.
small
large
longitudinal
shortening
circular
elongation
peristaltic
The Smooth Muscle Neuromuscular Junctions
• Very different from the skeletal muscle NMJ.
- Two types:
- Unitary NMJ:
- Hundreds to millions of muscle cells act as a functional unit.
• SMCs mechanically connected by desmosomes and electrically connected by gap junctions.
- Autonomic nerve cells do not make ____ with the SMCs: ____ junctions:
- Release of neurotransmitters into the ECM at some ____ from the cells: diffusion to reach target SMCs.
- Neurotransmitter released from ____: enlargements on the axon.
- E.g. ____ wall, ____ and many blood vessels.
Unitary > innervated by a ____ from the autonomous NS (functional unit), but it is not in direct contact with any of the cells > releases NTs from specialized structures > and disperse to the entire FU and they are induced to contract; all these cells are also connected via gap junctions and the diffusion spread via gap junction
SMC REACT TO TWO STIMULI: direct binding to ____, and the ____ between cells > result: contract/relax in a coordinated matter
direct contact diffuse distance varicosities gastrointestinal uterus
single neural termination
receptors
electrical gap junction
The SM Neuromuscular Junctions
Multiunit NMJ:
Each SMC is innervated ____: low cell- to-cell communication.
Nerve cell varicosities make ____ contact with the target SMCs: ____ junctions.
E.g. ____ muscle of the hair follicle, the ____ and ____ muscles of the eye.
The contact between neuron and cell is in direct contact but not as ____ as skeletal muscle
independently direct contact piloerector iris ciliary
intimate
Contraction and Excitation of Smooth Muscle
• SM contracts or relaxes in response to nerves and stimuli (striated muscle can only ____).
• Numerous possible inputs to contract or relax smooth muscle:
a. ____ nerves.
b. Circulating hormones: e.g. angiotensin, vasopressin.
c. ____ hormones (or paracrines): e.g. histamine, somatostatin, and
endothelin [potent vasoconstrictor]).
d. Ions and metabolites: e.g. O2 , CO2.
e. ____ from other cells: e.g. NO.
f. Signals from electrically-coupled SMCs.
g. ____ cues: e.g. stretch.
contract autonomic local signals mechanical
Contraction and Excitation of SM: Neuromuscular Transmission
Neuromuscular transmission in SM:
• ____ process (up to minutes).
• Commonly modulates ____
rhythmic activity.
Contraction/relaxation of smooth muscle can be initiated by:
- Intrinsic activity of ____ cells.
- Neural transmitters.
- Circulating or locally generated hormones or signaling molecules.
Multiunit muscles:
• No ____.
• ____ is most important.
Single unit muscles:
• ____ is propagated throughout the tissue.
Phasic contraction/relaxation > generate peristaltic movements [???}
Smooth muscle present in tissues that contain specialized cells (may not be ____) > that may regulate the pace of contraction
slow
spontaneous
pacemaker
electrical coupling
neural regulation
electrical activity
smooth muscle
Contraction and Excitation of Smooth Muscle: Membrane potentials
Resting Vm: -50 mV, (~ ____ higher than in skeletal muscle).
A. Spike potentials:
• Similar to those in skeletal muscle.
• Triggered by nerve stimulation, stretch or hormones; also
____.
• Single twitch or larger summed ____ responses.
• Characteristic of single-unit SM (e.g. ____).
• Gap junctions permit the spread of action potentials
throughout the tissue.
Much more negative potential in skeletal muscle cells
30
spontaneously
mechanical
visceral SM
Contraction and Excitation of Smooth Muscle: Membrane potentials
B. Slow waves:
• Rhythmic activity that may trigger action potentials.
• Not ____: fluctuations in membrane
potential from the activity of ____
(e.g. ____) in the cell membrane.
• Typical of the intestinal wall: important in ____.
Slow waves > ____, internal change in membrane potential due to variations in pumps working (pumping different rates at different times)
Sometimes the potential can be so depolarized that it is enough to cross the threshold and create an AP (NT has to induce traffic of ions, and if it is above threshold, more ions would enter and the depolarization would be even higher)
Cells contract ____ by themselves; waves are not AP, but sometimes the depolarization is so high that it induces the formation of an AP
action potentials
electrogenic umps
Na+/K+ ATPase
peristalsis
innate
spontaneously
Contraction and Excitation of SM: Membrane potentials
C. Graded changes in membrane potential:
____ contractile activity related to membrane potential in the absence of action potentials. Common in ____ (e.g., vasculature).
Never a creation in ____ > change in membrane potential > some degree of contraction/relaxation > variations in amount of ____, without the need to generate an AP
tonic
multiunit SM
AP
contractile force
Contraction and Excitation of Smooth Muscle: Membrane potentials
D. Action potential with plateau:
• Organs such as the ____.
• After rapid depolarization, repolarization is ____
by as much as 1 sec (SM remains contracted).
• A similar type of action potential occurs in ____.
____ stimulus to contract cell > very rapid depolarization (real AP); but the repolarization is delayed by up to a second > during this time there is a contractile force created without the need to repeat the stimulus
uterus
delayed
cardiac muscle
single
Smooth Muscle Physiology: Contractile Mechanism
- Different mechanism to striated muscle:
- Actin and myosin filaments not organized in ____.
- Shortening occurs between ____.
- Cell balloons out between ____ points.
- SM myosin ATPase activity is more than ____ lower than that of fast skeletal muscle myosin.
- SM can generate higher ____ and can ____ more than skeletal muscles (up to ____ of their resting length compared to ____ in skeletal muscles).
sarcomeres dense bodies dense body anchor 100-fold tension contract 30% 65%
Smooth Muscle Physiology: Contractile Mechanism
SMC fibers are connected electrically and mechanically > bt cells there are desmosomes, and ECM fibers (connective, not made by connective tissue but by ____) > connect cells mechanically (collagen, fibronectin, elastin and connected to integrins at level of PM), and also these molecules provide ____ to over stretching by collagen and ____ by elastin, and helps to maintain ____ by collagen, and conserve ____ during relaxation process by accumulating recoil energy from elastin helping the relaxation of the whole tissue
SMC resistance recoil structure energy
Excitation-Contraction Coupling in SM Cells: Liberation of Ca2+
• ____ is required for myofilament contraction.
• Ca2+ must be liberated from:
– Internal stores in the ____.
– External supply via ____ in the sarcolemma:
• ____ Ca2+ channels.
• ____ Ca2+ channels: independent of membrane depolarization.
• NO ____ in Smooth Muscle Cells.
• Major routes of Ca2+ entry and exit from
SM cytoplasm:
– Left: ↑[Ca2+] → contraction.
– Right: ↓[Ca2+] → relaxation
Calcium is required; not only liberated from SR stores, but most is imported from the ____
Voltage-gated channels (change in the polarization of the membrane will induce to open), and some are ligand-gated channel (not responding to AP, a ____ or GF though)
Ca++ SR channels voltage-gated ligand-gated T tubules EC matrix hormone
Smooth Muscle Contraction: Activation of MLC
In striated > Ca++ modifies troponin > tropomyosin, moves into groove of thin filament > now head of myosin can bind actin
inactive myosin > ____ protein chains (two HC w/ ____, and two LC w/ ____)
In smooth > Ca++ binds ____, this complex > ____ > transfers phosphate to ____ region
four ATPase domain regulatory domain calmodulin MLCK LC regulatory
Smooth Muscle Contraction: Activation of Myosin Light Chains
(MLCK)
Since Ca2+ control in smooth muscle is at the ____ filaments:
____ regulation
Inactive state > myosin tail is ____
Upon binding phosphate, the tail of myosin changes conformation (release of myosin tail) > active state > open ____ site on the head of the myosin HC > ____ (similar to striated muscle)
Control in striated was at thin cell > ____ regulation
Control in smooth is at thick cell > ____ regulation
thick
myosin-linked
disordered
actin-binding
bipolar filaments
actin-linked
myosin-linked
Smooth Muscle Contraction: Cross-bridge Cycle
- ATP is needed at ____ different points:
- One ATP to phosphorylate ____.
- One ATP per cycle of the ____.
- SM myosin ATPase activity is >100-fold lower than in striated muscle: ____ contraction.
- Phosphorylated cross-bridges cycle until myosin is dephosphorylated by a ____.
MLCK transfers phosphate to LC of myosin regulatory region > activated > can bind actin filaments > high-affinity for actin when domain is bound to ADP/Pi from previous cycle > power-stroke after release of both ADP/Pi > ATPase domain increases affinity for ATP and binds it thus releasing from thin filaments > hydrolyzes ATP, and prepares for the next cycle
Smooth muscle difference form striated > ____ > removes phosphate group that was added by MLCK; when active, eliminates phosphate, and myosin cannot bind actin (reverts back into inactive, disordered tail state)
In striated, did not need ____ to phosphorylate myosin
two myosin cross-bridge slow myosin LC phosphatase (MLCP)
myosin phosphatase
ATP
Contraction and Excitation of Smooth Muscle: The Latch State
• Latch state (or latch bridge):
• At full contraction, part of the phosphorylated
myosin is dephosphorylated by myosin light chain
phosphatase.
• Dephosphorylated myosin does not ____ from actin.
• SM stays contracted even though cross-bridge
cycling of dephosphorylated myosin molecules
does not occur (and no ATP is used).
• The latch bridge helps to maintain ____
with minimal ATP consumption.
immediately detach
muscular tone
The Latch State
• Myosin gets dephosphorylated by myosin phosphatase
- Myosin and actin remain attached
- ____ maintained
- No ____ needed
- Minimal energy utilization
Latch-state > ____ not increasing nor disappearing
Very cheap way of maintaining tone > doesn’t need to go through cross-bridge in order to maintain contraction
tone
ATP
contraction
Smooth Muscle Relaxation
• Ca2+ must be ____ to stop contraction.
• Two major ways:
– Sarcoplasmic reticulum: ____ pumps Ca2+ back into the SR.
– Sarcolemma: ____ and ____ export Ca2+ back to the extracellular space.
• Major routes of Ca2+ entry and exit from SM cytoplasm:
– Left: ↑[Ca2+] → contraction.
– Right: ↓[Ca2+] → relaxation.
Modulators that induce relaxation from even the tonic state > mediate exit of calcium > most of calcium will be exported back to the ____ > Na/Ca channels, sarcolemma located Ca ATPase, or a smooth muscle SERCA at membrane of SR > some of calcium stored back into the SR
removed
Ca++-ATPase
Na+/Ca++ exchanger
Ca++-ATPase
extracellular space
SM Contraction Summary
Contraction
- Ca2+ imported (mostly) from ____ and (less) from ____.
- Ca2+ binds ____.
- Ca2+-calmodulin activates ____.
- MLCK phosphorylates ____.
- Phosphorylated (active) myosin ____ and binds actin filaments: start of the ATP- dependent contraction cycle (cross-bridge).
- Contraction continues as long as myosin remains ____.
EC fluid SR calmodulin MLCK myosin light chain regulatory regions unfolds phosphorylated
Smooth Muscle Relaxation Summary
Relaxation
- Ca2+ levels are reduced by pumping back to the SR and extracellular fluid.
- Ca2+ liberates from ____, which inactivates ____.
- Myosin-light chain phosphatase (MLCP) dephosphorylates ____.
- Inactivation of myosin ATPase stops the cross-bridge cycle.
calmodulin
MLCK
regulatory myosin light chains
Neural Control: G-protein coupled receptor pathway
- GPCR-mediated contraction:
- Muscarinic acetyl choline receptor (mAChR, typically ____):
- Typical of ____ muscle.
- Binding of ____).
- α1 adrenergic receptor (α1R):
- ____.
- Binding of ____ (epinephrine and norepinephrine).
• Both: Activation of ____ → production of ____ and ____
- Mechanisms of contraction:
- Release of Ca2+ from the ____.
- Inhibition of K+ channels, preventing hyperpolarization of the sarcolemma.
These receptors will activate the GPCR > activates a series of phospholipase (C ) > production of IP3 > binds to a receptor in the SR, which is a ____ calcium channel > exports calcium from internal stores > induces contraction
No measure of AP > dependent totally on ligands, no ____
M3
GI smooth
ACh
BV
catecholamines
phospholipases
IP3
DAG
SR
receptor
electrical activity
Neural Control: cAMP pathway
- β-adrenergic relaxation:
- ____ smooth muscles:
- Adjustment of ____ and ____.
- Response to ____ (epinephrine and norepinephrine).
- Activation of ____ and formation of cAMP.
- cAMP can be inactivated to AMP by a ____.
- Mechanisms of relaxation:
- ____ phosphorylation (inactivation) of MLCK.
- Stimulation of Ca2+ reuptake by the SR (not shown).
Dropping blood pressure, increasing blood flow [???]
vascular
blood flow
pressure
catecholamines
adenylyl cyclase
phosphodiesterase (PDE)
cAMP-dependent protein kinase (PKA)
Neural Control: cAMP Pathway
Epi and norepinephrine binds B2 > formation of cAMP from adenylate cyclase activation > PKA > phospho MLCK > inactive
Even if calcium is present, the activity of MLCK will be lower > cannot bind to the complex > cannot induce phospho of myosin > INDEPENDENT OF THE ____ > relaxation of SMC
calcium concentration
NE released by sympathetic system > acts on SMC located in BV in the GI/stomach > ____ > activates GPCR pathway > contraction (vasoconstriction); however, in lung, NE binds ____ > relaxation
In gut/stomach, ACh binds ____ > peristalsis; in lung, ACh binds ____ > constriction
Depending on the ____ of the SMC > the end effect of the cell is completely opposite/different (completely different pathways)
A1R
B2
MAchR
MAchR
receptor
Neural Control: NO pathway
• Nitric Oxide (NO) relaxation:
• ____ smooth muscles:
• Adjustment of ____ and ____.
• Response to NO produced by ____ cells.
• Activation of ____ which produces cGMP.
• cGMP can be inactivated to GMP by a ____.
- Mechanisms of relaxation:
- cGMP-dependent protein kinase (PKG) activation of ____.
- Prevents entry and promotes reuptake Ca2+.
- Opens K+ channels that hyperpolarize the sarcolemma.
NO produced by NO synthase > guanylate cyclase > cGMP > PKG > acts on ____ > activates it > converts active myosin into inactive > relaxation
small artery blood flow pressure guanylyl cyclase phosphodiesterase (PDE)
MLC phosphatase
MLC phosphatase
Smooth Muscle Contractile Activity Patterns
• Essential difference with skeletal muscle: Smooth muscle can ____ or ____ in response to a stimulus.
- Tonic smooth muscles:
- Continuously ____: normally contracted.
- ____ steady-state force.
- ____, blood vessels, and airways.
• Phasic smooth muscles:
• ____ contractions:
• Walls of the ____ and urogenital
tracts.
• Normally relaxed smooth muscles:
• May contract intermittently during physiological
activities under ____ control:
• Voiding of ____ and swallowing.
In sphincters, induced to relax completely or contracted
GI/stomach > phasic activity > contraction or relaxation > induce persistalsis
SMC in the esophagus, usually relaxed, but contract when we voluntarily swallow something
contract relax active variable sphincters
rhythmic
GI
voluntary
urine
Smooth Muscle Mechanical Properties
- From ____ measurements: Length-tension relationship:
- Similar to skeletal muscle: mainly due to the degree of ____ of thin and thick filaments.
- One difference: SM has more connective tissue and thus has more ____.
- SM operates over a ____ of resting lengths than striated muscles.
isometric
overlapping
passive force
wider range
Smooth Muscle Mechanical Properties
From ____ measurements: Force-velocity relationship:
Similar in overall ____ in smooth and skeletal muscles:
– Depends on load.
– ____ at zero load.
- Differences:
- Lower ____ of contraction: due to lower ATPase activity of SM myosin.
Inverse relationship graph similar to what was seen last week
isotonic
shape
maximal
velocity
Smooth Muscle Mechanical Properties
• Differences:
• Lower velocity of contraction: due to lower ATPase activity of SM myosin.
• ATPase activity depends on ____: changes in degree of phosphorylation will affect ____ as well as ____ generated.
Filament can contain phos and non-phos myosin heads; degree of phos it can be very high or very low
If most myosin molecules are phospho > 60%: greatest curve; if only 10% > lowest curve; ____ of containing 10% is much lower, because only phos molecules are active
Not phospho > the ____ (x-axis) generated from the SMC is very low
phosphorylation
velocity
maximal stress
velocity
force
Smooth Muscle Adaptation
- Hormone-induced hypertrophy:
- Typical of ____.
- ____induced on SM-rich uterine myometrium (up to 70-fold).
- Increase in ____ and ____.
- Other forms of hypertrophy:
- Blood vessels: due to ____.
- Urinary bladder, small intestine: due to ____.
- Phenotypic transformation:
- Switch from contractile to synthesizing phenotype (of collagen, elastin, LDLs).
- Typical of ____ and ____.
Conversion of contractile to synthesizing > change ____ pattern > remove contractile mechanisms, and only produce substances (ECM proteins) > fibrosis (pathological response to ____ or invasion of ____)
pregnancy
progesterone and estrogen
muscle size (hypertrophy)
cell number (hyperplasia)
chronic hypertension
chronic obstruction
fibroses
artherosclerosis
gene expression
chronic inflammation
toxin
Skeletal vs. Smooth Muscles
Skeletal Muscle:
Made of \_\_\_\_ myofibers. Striated myofibers are large and \_\_\_\_: average length = \_\_\_\_ average diameter = \_\_\_\_ No \_\_\_\_ among cells. \_\_\_\_ types of myosin (fast and slow) and \_\_\_\_ types of muscles (fast and slow) Glycolytic and oxidative metabolism (relatively inefficient). \_\_\_\_. Upon stimulation, muscles can only \_\_\_\_.
Smooth Muscle:
Smooth muscle cells (no ____). Cells are small and ____:
average length = ____
average diameter = ____
Cells are connected ____ via desmosomes and ____ via gap junctions.
____ type of myosin (slow myosin produced by the Slow Myosin gene).
Energy from oxidative metabolism (____ times more efficient than skeletal muscle).
____.
Exhibit ____ (i.e. prolonged contraction with minimal use of energy).
Upon stimulation, SMs can either ____ or ____.
striated multinucleated cm 100-200 um connections two two voluntary contract
cross-striations single-nucleated 50-500 um 2-10 um mechanically functionallysingle 10-300x involuntary tone contract relax
