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PHYSL 404 - Cardiovascular Physiology > 8/9 - Vascular Smooth Muscle Cells > Flashcards

8/9 - Vascular Smooth Muscle Cells Flashcards

1
Q

Contraction of smooth muscles can be _____ or ______

A

Contraction of smooth muscles can be tonic or phasic

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2
Q

What is tonic contraction?

A
  • Tonic
    • Slow and sustained contractions
      • can maintain force for prolonged time with only little energy utilization
        • eg respiratory, urinary tract, skin, eye and vasculature
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3
Q

What is phasic contraction?

A
  • Phasic
    • Rapid contractions and relaxations
      • eg digestive tract
        • the phasic contraction of the smooth muscles in the GIT generates rhythmic peristaltic contractions
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4
Q

Lable the three layers of the vasculature and the vascular smooth muscle cells

A
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5
Q

What is the tunica adventitia?

A

Outermost layer of vasculature

Contains some elastic fibres, collagen fibres and fibroblasts

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6
Q

What is the Tunica media?

A

Middle layer of vasculature

contains elastic fibres, collagen fibres, and smooth muscle

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7
Q

What is the tunica intima?

A

Innermost layer of the vasculature

Contains collagen and endothelial cells

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8
Q

What is the structure of vascular smooth muscle cells?

A
  • Non-striated
  • Spindle-shaped
  • No sarcomere structure, but bundles of filaments
  • Filament structures:
    • dense bodies, actin, myosin filaments, intermediate filaments
  • The contractile units are anchored to the dense bodies (rich in alpha-actinin)
  • The intermediate-sized filaments (non-contractile) connect the dense bodies/contractile units (actin-myosin) to the cytoskeleton thereby synchronizing the contraction of the contractile units to generate whole cell contraction
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9
Q

What are the filament structures in vascular smooth muscle cells (4)

A
  1. dense bodies
  2. actin
  3. myosin filaments
  4. intermediate filaments
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10
Q

The contractile units of vascular smooth muscle cells are anchored to the _________ which are rich in ______

A

The contractile units of vascular smooth muscle cells are anchored to the dense bodies which are rich in alpha-actinin

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11
Q

What connects the dense bodies/contractile units (actin/myosin) to the cytoskeleton? What does this connection establish?

A
  • intermediate-sized filaments (non-contractile) connect the dense bodies/contractile units (actin-myosin) to the cell cytoskeleton
  • Connection synchronizes the contraction of the contractile units to generate whole-cell contraction
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12
Q

Dense bodies are rich in _______ and serve as cytoplasmic anchors for ________. they attach to _________ and connect them together

A

Dense bodies are rich in alpha-actinin and serve as cytoplasmic anchors for thin filaments (actin). they attach to intermediate filaments and connect them together

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13
Q

What are membrane adhesion complexes?

A

Junctions where actin filaments are connected to integrin proteins via “linker” proteins within the adhesion complexes such as alpha-actinin, talin, paxillin, vinculin, and filamin

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14
Q

Adhesion complexes of smooth muscle cells (SMC) are not static, they are _________ during contractile stimulation which triggers association of ________ with _________

A

Adhesion complexes of smooth muscle cells (SMC) are not static, they are dynamically regulated during contractile stimulation which triggers association of adhesion molecules with beta-integrins

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15
Q

What makes up the contractile unit of smooth muscle cells

A
  • Thick filaments (15-18nm)
    • predominantly myosin heavy chains (MHC)
    • Myosin light chains (MLC)
  • Thin filaments (6-8nm)
    • Polymerized actin with tropomyosin attached to dense bodies
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16
Q

Intermediate filaments are predominantly ________ and ________

  • Regulate ______ and ________ of SMCs
  • Insert into _____ along with _____
  • Facilitate ___________ that optimizes force generation
A

Intermediate filaments are predominantly vimentin and desmin

  • Regulate shape and spatial organization of SMCs
  • Insert into dense bodies along with actin
  • Facilitate spatial reorganization that optimizes force generation
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17
Q

Thick filament (myosin II) is comprised of:

A
  • 2 myosin heavy chains (MHC)
    • globular head (N-terminus), neck and alpha-helical tail portion (c-terminus)
  • 4 Myosin light chains (MLC)
    • 2 essential light chains (ELC) contribute to structural stability of myosin head
    • 2 regulatory light chains (RLC) contain activating/inhibitory phosphorylation sites
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18
Q

What are the structural components of thin (actin) filament

A
  • thin (actin) filament is comprised of
    • alpha-actin
    • tropomyosin
    • calponin
    • caldesmon
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19
Q

_______ is the primary form of actin in smooth muscle cells

A

alpha-actin is the primary form of actin in smooth muscle cells

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20
Q

Tropomyosin expands over __________

A

Tropomyosin expands over 7 actin monomers (function in SMC unknown)

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21
Q

SMC do NOT have the ______ (unlike cardiomyocyte and skeletal muscle)

A

SMC do NOT have the troponin complex (unlike cardiomyocyte and skeletal muscle)

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22
Q

Instead of troponin what do SMC have?

A

Instead of Tn, SMC have calponin and caldesmon

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23
Q

_______, ______ and ______ inhibit the ATPase activity of the myosin complex that otherwise provides energy for SMC contraction

A

Tropomyosin, calponin and caldesmon inhibit the ATPase activity of the myosin complex that otherwise provides energy for SMC contraction

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24
Q

What is calponin?

A
  • A load-bearing 32kDa protein
  • inhibits the ATPase activity of myosin
  • interacts with actin monomer at a distinct site between CH and CaP in a 1:1 ratio

CH = calponin homology domain

CaP = calponin repeats

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25
Q

What inhibits the binding of calponin to actin to relive the inhibition of myosin ATPase (thus allowing SMC contraction)?

A

phosphorylation of calponin (by CaMK or PKC)

or Ca++/calmodulin binding to calponin CH (not tropomyosin)

inhibits its binding to actin to relieve inhibition of ATPase activity and allow SMC contraction

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26
Q

What is Caldesmon?

A

Caldesmon (CAD or CaD)

  • 87 kDa alpha-helical protein similar to calponin
  • Tethers actin, myosin and tropomyosin
  • one caldesmon molecule interacts with 16 actin monomers
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27
Q

What causes the C-terminal domain of caldesmon (CAD) to be repositioned on the actin? What does this repositioning allow?

A

Phosphorylation of CAD or Ca++/calmodulin binding to CAD repositions its C-terminal domain on the actin

  • Allows myosin to bind the actin
  • Relieves inhibition on myosin ATPase
  • leads to SMC contraction
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28
Q

What are the 6 steps of MLC activation and SMC contraction in the diagram?

A
  • Ca++ enters the SMC = more Ca++ released from SR = intracellular Ca++ levels rise
  • Free Ca++ binds to a special calcium binding protein called calmodulin
  • Calcium-calmodulin (Ca/CaM) activates myosin light chain kinase (MLCK)
  • MLCK phosphorylates the regulatory subunit (RLC) on the myosin light chains in the presence of ATP
  • Ca/CaM also relieves the inhibitory effect of calponin and caldesmon in myosin-actin interacion
  • MLC phosphorylation leads to cross bridge formation between the myosin heads and the actin filament, leading to SMC
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29
Q

___________-mediated myosin activation initiates smooth muscle contraction

A

calmodulin-mediated myosin activation initiates smooth muscle contraction

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30
Q

What is Calmodulin?

A
  • CALcium MODULating proteIN
  • a Ca++ binding intracellular messenger protein (binds to four Ca++ ions)
  • Has two almost symmetrical globular domains (N- and C-terminus) separated by a very flexible linker region
  • The flexibility of the linker region allows CaM to ‘wrap’ itself around its target (eg MLCK)
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31
Q

What is Myosin Light Chain Kinase?

A
  • A serine/threonine-specific protein kinase that phosphorylates the regulatory light chain of myosin II (RLC)
  • In SMC, MLCK phosphorylates MLC at serine 19 which allows myosin cross-bridge binding to actin
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32
Q

In SMC, MLCK phosphorylates MLC at _______ which allows myosin cross-bridge binding to actin

A

In SMC, MLCK phosphorylates MLC at serine 19 which allows myosin cross-bridge binding to actin

33
Q

_________ of the regulatory light chain by ______ promotes the cross-bridge cycling

A

Phosphorylation of the regulatory light chain by MLCK promotes the cross-bridge cycling

34
Q

VSMC contraction and relaxation mediates vascular _____ and ______

A

VSMC contraction and relaxation mediates vascular constriction and dilation

35
Q

What is the function of myosin light chain phosphatase (MLCP)?

A
  • It opposes the function of MLCK
  • dephosphorylates MLC and inhibits SMC contraction
  • Its activity is inhibited by RhoA and Rho kinase
36
Q

The activity of myosin light chain phosphatase (MLCP) is inhibited by:

A

RhoA and Rho kinase

37
Q

What is the structure of Myosin light chain phosphatase (MLCP)

A
  • MLCP is composed of 3 subunits:
    • Large substrate (myosin) targeting subunit called myosin phosphatase targeting subunit (MYPT1)
    • A catalytic subunit - dephosphorylates pRLC
    • a small subunit with unknown function
38
Q

What inhibits MLCP (myosin light chain phosphatase) activity?

A

Phosphorylation on Thr697 and Thr855 by RhoK (ROK) inhibits MLCP activity

39
Q

What are three factors that trigger VSMC contraction?

A
  • Agonist stimulation
    • G-protein coupled receptors (GPCR)
    • Tyrosine Kinase Receptors (TKR)
  • Mechanical stress (stretch)
  • Ca++-independent contraction
40
Q

What does the image show?

A

VSMC contraction induced by a GPCR ligand

41
Q

What are three GPCR agonists that lead to VSMC contraction and which receptor do they act on

A
  • Norepinephrine (NE)
    • alpha1-adrenoreceptor (alpha-1AR)
  • Angiotensin II (AII or Ang II)
    • Angiotensin II receptor type 1 (AT1)
  • Endothelin 1 (ET1)
    • Endothelin receptor type A (ETA)
42
Q

Which GPCR leads to formation of DAG and IP3?

A

Galpha-q

43
Q

How does Galpha-q lead to IP3 and DAG?

A

Gq → PLC → IP3 and DAG

IP3 → Ca++

DAG → PKC

44
Q

What is PIP2?

A

Phosphatidyl inositol 4,5-biphosphoate

  • minor phospholipid component of the cell membrane
  • enriched at the plasma membrane where it is a substrate for a number of signaling proteins (eg PLC)
45
Q

What is the action of PLC on PIP2?

A

PLC catalyzes (hydrolyses) PIP2 into 2 second messengers:

  1. IP3 (inositol 1,4,5-triphosphate) and
  2. DAG (diacylglycerol)
46
Q

What IP3 receptors are found in vascular smooth muscle cells and skeletal muscle?

A

IP3R1

47
Q

What IP3 receptors are found in vascular endothelial cells?

A

IP3R2 and IP3R3

48
Q

The amount of Ca++ released from IP3R is directly dependent on ____

A

The amount of Ca++ released from IP3R is directly dependent on [IP<u>3</u>]

49
Q

What are TKRs?

A

Tyrosine Kinase Receptors

  • high affinity cell surface receptors for many polypeptide growth factors, cytokines and hormones
50
Q

What happens upon binding of a ligand to TKR?

A
  • Ligand binding to tyrosine kinase receptor
    • receptors are dimerized and tyrosine residues are phosphorylated
  • Inactive intracellular proteins (with src-homology domain) bind tot eh activated receptor and become activated (eg Ras-raf, Pl3K, PLCgamma)
    • subsequently activating a number of intracellular signaling pathways
51
Q

What is the outcome of TKR activation?

A
  • Outcome of TKR activation is acute as well as long-term
  • the intracellular signaling proteins that can be activated by TKR (or RTK) include PI3K, PLCgamma and Ras
52
Q

Which intracellular signaling proteins can be activated by TKR?

A

the intracellular signaling proteins that can be activated by TKR (or RTK) include PI3K, PLCgamma and Ras

53
Q

PI3K, PLCgamma and Ras can lead to:

A
  • cell proliferation
  • enzyme activation
  • apoptosis
  • activation of transcription factors
  • many more cellular events
54
Q

________ is involved in acute phase of vasocontriction

A

actin polymerization is involved in acute phase of vasocontriction

55
Q

What is actin polymerization

A

Incorporation of monomeric G-actins into F-actin fibres

56
Q

Actin filaments are linked to integrins via _____ and ______

A

Actin filaments are linked to integrins via Alpha-actin and talin (actin cross-linking protiens)

57
Q

Mechanical strain is sensed by _____

A

Integrins - receptors that link the cell membrane to the ECM

58
Q

Actin polymerization requires _________ and involves a number of _________

A

Actin polymerization requires paxillin phosphorylation and involves a number of focal adhesion proteins (eg alpha-actinin, talin, paxillin, vinculin and FAK)

59
Q

___ mediated signaling in SMCs is Ca++ independent

A

_RhoA-_mediated signaling in SMCs is Ca++ independent

60
Q

What are the critical sites of activity of MYPT1 (myosin binding domain of MLCP)

A
  • pRLC binding site
  • Phosphorylation sites that when phosphorylated can cause a conformation change that inhibits the access of pRLC to the substrate binding site
    • eg ROK can phosphorylate Thr697 and Thr855 thereby inhibiting MLCP activity
61
Q

The catalytic subunit (PP1c) of MLCP can be directly inhibited by _____

A

The catalytic subunit (PP1c) of MLCP can be directly inhibited by CPI-17-P

62
Q

MLCP can be regulated by _______ and ______

A

MLCP can be regulated by RhoKinase and CPI-17-p

63
Q

What are the steps to Smooth muscle contraction as shown in the image

A
  • Intracellular Ca++ concentrations increase when Ca++ enters cell and is released from SR
  • Ca++ binds to calmodulin (CaM)
  • Ca++-calmodulin activates myosin light chain kinase (MLCK)
  • MLCK phosphorylates light chains in myosin heads and increases myosin ATPase activity
  • Active myosin crossbridges slide along actin and create muscle tension
64
Q

What are the steps to smooth muscle relaxation as shown in the image?

A
  1. Free Ca++ in cytosol decreases when Ca++ is pumped out of the cell or back into the SR
  2. Ca++ unbinds from calmodulin (CaM)
  3. Myosin phosphatase removes phosphate from myosin, which decreases myosin ATPase activity
  4. Less myosin ATPase results in decreased muscle tension
65
Q

What are four ion channels in VSMC

A
  1. Voltage-activated Ca-channel
  2. Stretch-activated Ca-channel
  3. Large conductance, Ca-activated K-Channel
  4. Voltage activated K-channel
66
Q

What are four Ca++ channels in vascular smooth muscle cells?

A
  • Voltage dependent (VDCC)
  • Store-operated (SOC - opens to replenish the Ca++ in SR)
  • Receptor operated (ROC - opens in response to receptor activation)
  • Stretch activated (SACC - responds to mechanical stretch)
67
Q

IP3R - present on the ___, releases ____. Dependent on _____

A

IP3R - present on the SR, releases Ca++. Dependent on [IP3]<u>i</u>

68
Q

What are three potassium channels in vascular smooth muscle cells?

A
  • Large conductance Ca++-activated (BKCa)
  • Voltage-gated (by depolarization) (Kv)
  • ATP-activated (KATP)
69
Q

What is the structure of BKCa channels (large-conductance Ca-activated K-channels)

A
  • alpha subunit
    • 7 tmd (S0-S6)
      • extracellular N and intracellular C
    • 3 Ca++ binding sites in the C-terminus: RCK1, RCK2, and Ca++ bowl
    • S0 segment is critical in interaction with the beta-subunit in regulation of channel gating
  • beta subunit
    • two TMD and one extracellular loop
    • present in 1:1 ratio with alpha subunit
    • increases sensitivity of the channel to [Ca++]
    • Four different isoforms identified so far, Beta1 is principle form in VSM
70
Q

What is the structure of the alpha subunit of BKCa

  • alpha subunit
    • ____ TMD (S_-S_)
      • ______ N and ______ C
    • _____ binding sites in the -terminus: ___, ____, and _____
    • S0 segment is critical in interaction with the_____ in regulation of ______
A
  • alpha subunit
    • 7 tmd (S0-S6)
      • extracellular N and intracellular C
    • 3 Ca++ binding sites in the C-terminus: RCK1, RCK2, and Ca++ bowl
    • S0 segment is critical in interaction with the beta-subunit in regulation of channel gating
71
Q

What is the structure of the beta-subunit of BKCa

  • beta subunit
    • two ___ and one _____\_
    • present in 1:1 ratio with______
    • increases sensitivity of the channel to _____\_
    • Four different isoforms identified so far, _____\_ is principle form in VSM
A

What is the structure of the beta-subunit of BKCa

  • beta subunit
    • two TMD and one extracellular loop
    • present in 1:1 ratio with alpha subunit
    • increases sensitivity of the channel to [Ca++]
    • Four different isoforms identified so far, Beta1 is principle form in VSM
72
Q

Genetic loss of beta-subunit of BKCa channel causes:

A

Increased VSM contractility and hypertension (in mice)

73
Q

Gain of function mutation of BKCa causes:

A

Lower blood pressure (humans)

74
Q

What are caveolae?

A

invaginations in the SMC plasma membrane (similar to T-tubules in cardiomyocytes)

Caveolins are a family of membrane proteins and the principle component of caveolae

75
Q

The principle component of caveolae are _______

A

The principle component of caveolae are caveolins

76
Q

A number of signaling molecules are anchored tot eh caveolae through binding to the _____ protein

A

A number of signaling molecules are anchored tot eh caveolae through binding to the Cav-1 protein

eg: g-protein subunits, RTK and small GTPases

77
Q

Caveolae are in close proximity to the ____ and take part in ______

A

Caveolae are in close proximity to the SR and take part in intracellular calcium homeostasis

78
Q

________ reside in the caveolae of arterial smooth muscle cells; hyperactivity of which can lead to ______

A

hormonal receptors (GPCRs) reside in the caveolae of arterial smooth muscle cells; hyperactivity of GPCRs can lead to hypertension

79
Q

Hyperactivity of GPCRs can be triggered by:

A

Increased Na+

PHYSL 404 - Cardiovascular Physiology (17 decks)

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