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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
What inhibits the binding of calponin to actin to relive the inhibition of myosin ATPase (thus allowing SMC contraction)?
**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
26
What is Caldesmon?
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
27
What causes the C-terminal domain of caldesmon (CAD) to be repositioned on the actin? What does this repositioning allow?
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
28
What are the 6 steps of MLC activation and SMC contraction in the diagram?
* 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
29
\_\_\_\_\_\_\_\_\_\_\_-mediated myosin activation initiates smooth muscle contraction
_calmodulin_-mediated myosin activation initiates smooth muscle contraction
30
What is Calmodulin?
* 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)
31
What is Myosin Light Chain Kinase?
* 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
32
In SMC, MLCK phosphorylates MLC at _______ which allows myosin cross-bridge binding to actin
In SMC, MLCK phosphorylates MLC at **_serine 19_** which allows myosin cross-bridge binding to actin
33
\_\_\_\_\_\_\_\_\_ of the regulatory light chain by ______ promotes the cross-bridge cycling
_Phosphorylation_ of the regulatory light chain by _MLCK_ promotes the cross-bridge cycling
34
VSMC contraction and relaxation mediates vascular _____ and \_\_\_\_\_\_
VSMC contraction and relaxation mediates vascular _constriction_ and _dilation_
35
What is the function of myosin light chain phosphatase (MLCP)?
* It opposes the function of MLCK * dephosphorylates MLC and inhibits SMC contraction * Its activity is inhibited by RhoA and Rho kinase
36
The activity of myosin light chain phosphatase (MLCP) is inhibited by:
RhoA and Rho kinase
37
What is the structure of Myosin light chain phosphatase (MLCP)
* 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
What inhibits MLCP (myosin light chain phosphatase) activity?
Phosphorylation on Thr697 and Thr855 by RhoK (ROK) inhibits MLCP activity
39
What are three factors that trigger VSMC contraction?
* Agonist stimulation * G-protein coupled receptors (GPCR) * Tyrosine Kinase Receptors (TKR) * Mechanical stress (stretch) * Ca++-independent contraction
40
What does the image show?
VSMC contraction induced by a GPCR ligand
41
What are three GPCR agonists that lead to VSMC contraction and which receptor do they act on
* 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
Which GPCR leads to formation of DAG and IP3?
Galpha-q
43
How does Galpha-q lead to IP3 and DAG?
Gq → PLC → IP3 and DAG IP3 → Ca++ DAG → PKC
44
What is PIP2?
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
What is the action of PLC on PIP2?
PLC catalyzes (hydrolyses) PIP2 into 2 second messengers: 1. IP3 (inositol 1,4,5-triphosphate) and 2. DAG (diacylglycerol)
46
What IP3 receptors are found in vascular smooth muscle cells and skeletal muscle?
IP3R1
47
What IP3 receptors are found in vascular endothelial cells?
IP3R2 and IP3R3
48
The amount of Ca++ released from IP3R is directly dependent on \_\_\_\_
The amount of Ca++ released from IP3R is directly dependent on _[IP_3_]_
49
What are TKRs?
Tyrosine Kinase Receptors * high affinity cell surface receptors for many polypeptide growth factors, cytokines and hormones
50
What happens upon binding of a ligand to TKR?
* 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
What is the outcome of TKR activation?
* 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
Which intracellular signaling proteins can be activated by TKR?
the intracellular signaling proteins that can be activated by TKR (or RTK) include PI3K, PLCgamma and Ras
53
PI3K, PLCgamma and Ras can lead to:
* cell proliferation * enzyme activation * apoptosis * activation of transcription factors * many more cellular events
54
\_\_\_\_\_\_\_\_ is involved in acute phase of vasocontriction
_actin polymerization_ is involved in acute phase of vasocontriction
55
What is actin polymerization
Incorporation of monomeric G-actins into F-actin fibres
56
Actin filaments are linked to integrins via _____ and \_\_\_\_\_\_
Actin filaments are linked to integrins via _Alpha-actin_ and _talin_ (actin cross-linking protiens)
57
Mechanical strain is sensed by \_\_\_\_\_
Integrins - receptors that link the cell membrane to the ECM
58
Actin polymerization requires _________ and involves a number of \_\_\_\_\_\_\_\_\_
Actin polymerization requires _paxillin phosphorylation_ and involves a number of _focal adhesion proteins_ (eg alpha-actinin, talin, paxillin, vinculin and FAK)
59
\_\_\_ mediated signaling in SMCs is Ca++ independent
_RhoA-_mediated signaling in SMCs is Ca++ independent
60
What are the critical sites of activity of MYPT1 (myosin binding domain of MLCP)
* 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
The catalytic subunit (PP1c) of MLCP can be directly inhibited by \_\_\_\_\_
The catalytic subunit (PP1c) of MLCP can be directly inhibited by _CPI-17-P_
62
MLCP can be regulated by _______ and \_\_\_\_\_\_
MLCP can be regulated by _RhoKinase_ and _CPI-17-p_
63
What are the steps to Smooth muscle contraction as shown in the image
* 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
What are the steps to smooth muscle relaxation as shown in the image?
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
What are four ion channels in VSMC
1. Voltage-activated Ca-channel 2. Stretch-activated Ca-channel 3. Large conductance, Ca-activated K-Channel 4. Voltage activated K-channel
66
What are four Ca++ channels in vascular smooth muscle cells?
* 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
IP3R - present on the \_\_\_, releases \_\_\_\_. Dependent on \_\_\_\_\_
IP3R - present on the _SR_, releases _Ca++_. Dependent on _[IP3]_i
68
What are three potassium channels in vascular smooth muscle cells?
* Large conductance Ca++-activated (BKCa) * Voltage-gated (by depolarization) (Kv) * ATP-activated (KATP)
69
What is the structure of BKCa channels (large-conductance Ca-activated K-channels)
* 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
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 \_\_\_\_\_\_
* 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
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
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
Genetic loss of beta-subunit of BKCa channel causes:
Increased VSM contractility and hypertension (in mice)
73
Gain of function mutation of BKCa causes:
Lower blood pressure (humans)
74
What are caveolae?
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
The principle component of caveolae are \_\_\_\_\_\_\_
The principle component of caveolae are _caveolins_
76
A number of signaling molecules are anchored tot eh caveolae through binding to the _____ protein
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
Caveolae are in close proximity to the ____ and take part in \_\_\_\_\_\_
Caveolae are in close proximity to the _SR_ and take part in _intracellular calcium homeostasis_
78
\_\_\_\_\_\_\_\_ reside in the caveolae of arterial smooth muscle cells; hyperactivity of which can lead to \_\_\_\_\_\_
_hormonal receptors (GPCRs)_ reside in the caveolae of arterial smooth muscle cells; hyperactivity of GPCRs can lead to _hypertension_
79
Hyperactivity of GPCRs can be triggered by:
Increased Na+

PHYSL 404 - Cardiovascular Physiology (17 decks)

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