Vascular Smooth Muscle Contraction and Regulation Flashcards
Excitation-Contraction coupling in smooth muscle
1) Most important: NE binding to alpha/beta receptor; less important:AP causes voltage-gated Ca2+ channels to open and influx of Ca2+
1a) Ligand-gated Ca2+ channels in sarcolemmal membrane may be opened by hormones or NTs, letting more Ca2+ in
1b) IP3-gated Ca2+ release channels in sarcoplasmic reticulum may be opened by hormones and NTs, letting more Ca2+ in
2) Ca2+ (4 molecules) binds calmodulin, and Ca2+/calmodulin complex binds and activates myosin-light-chain kinase (MLCK)
3) MLCK phosphorylates myosin light chain, changing the conformation of myosin head
4) Myosin binds actin, hydrolyzes ATP, and forms cross-bridge and produces tension
(Also Ca2+/calmodulin phosphorylates calponin and caldesmon which releases them from actin and allow activity of myosin ATPase and interaction between actin and myosin)
During relaxation of smooth muscle, what causes fall of intracellular Ca2+
Activation of myosin-light-chain phosphatase (MLCP), which dephosphorylates myosin light chain
Hyperpolarization closes voltage-gated Ca2+ channels
Direct inhibition of Ca2+ channels by ligands like cAMP and cGMP
Inhibition of IP3 production and decreased release of Ca2+ from sarcoplasmic reticulum
Increased Ca2+ ATPase activity in SR
Voltage-gated Ca2+ channels
In sacrolemmal (plasma) membrane of smooth muscle cell
Open when cell membrane potential depolarizes and cause AP
Ligand-gated Ca2+ channels
In sarcolemmal (plasma) membrane of smooth muscle cell
Hormones and NTs bind to receptors that are coupled to Ca2+ channel via G-protein
IP3-gated sarcoplasmic reticulum Ca2+ channels
NE binds alpha1 receptor in sarcolemmal (plasma) membrane –> G-protein coupled to phospholipase C –> PLC turns PIP2 to IP3 and DAG –> IP3 diffuses to SR and opens SR IP3 receptor Ca2+ channels (IP3R) –> Ca2+ flows out of SR and into cytoplasm
IP3-gated channels are in SR, so are similar to RyR
Normal values for preload and afterload
RV preload: 2-8 mmHg
RV afterload: (15-30)/(5-15) mmHg (pulm artery syst/diast)
LV preload: 4-12 mmHg
LV afterload: (100-140)/(60-90) mmHg (arterial syst/diast)
Normal LV contractility
55-70% ejection fraction
Normal cardiac output
5-6 L/min
What does epinephrine at low physiological levels do?
Vasodilation (by binding beta2 receptors)
(At HIGH epi concentrations, it binds alpha1 receptors and causes vasoconstriction)
Vascular smooth muscle (VSM) cells
Contains thick (myosin) and thin (actin) filaments which are randomly aligned
Cells around vessels perpendicular to vessel axis
Dense bodies hold contractile proteins to each other and cell surface
VSM use same sliding filament mechanism but do it >10x slower
Have some titin but more collagen and elastin
Has tropomyosin but NO troponin
Sparse SR come in contact with caveolae
How are VSM cells innervated?
ONLY by sympathetic fibers!
(except sex organs)
Multiunit smooth muscle
Each cell (or every few) has own nerve varicosity
Often don’t require AP to contract
In large arteries, veins, sphincters
MOST VSM are multiunit
Single unit smooth muscles
Electrical communication via gap junctions
In arterioles and helpatic portal vein
Myosin light chain phosphatase (MLCP)
Dephosphorylates myosin light chain to inactivate is and promote relaxation
PKG activates MLCP by phosphorylating it (muscle relaxation)
PKC inhibits MLCP by phosphorylating it (muscle contraction)
DAG
DAG activates PKC
PKC phosphorylates L-type Ca2+ channels so Ca2+ influx
PKC phosphorylates K+ channels, decreasing their conductance and depolarizing membrane
PKC phosphorylates and activates MLCP to cause contraction
What do PKA, PKG, and PKC do to contraction?
PKC increases force of contraction
PKA and PKG decrease force of contraction
Phosphorylated L-type Ca2+ channels
Exist in sarcolemma
More likely to be open at any given voltage
So, promotes contraction
Note: phosphorylated by PKC
(Normal L-type Ca2+ channels threshold at -55mV, but phosphorylated would be lower)
Voltage-gated K+ channels in smooth muscle (gK, v)
“Delayed rectifier”
gK increases with depolarization more than 40mV
Has incomplete inactivation and speeds repolarization after cell depolarization
ATP sensitive K+ channels in smooth muscle (gK, ATP)
Senses low ATP, high ADP, low pH, adenosine (things that happen during ischemia) –> closure of L-type Ca2+ channels –> hyperpolarization –> VSM dilates/relaxes
Channels in most arteries, arterioles, veins, coronary arteries
Phosphorylated by PKA, PKG –> relaxation
Phosphorylated by PKC –> constriction
Calcium channel blockers
Nifedipine
Diltiazem
Verapamil
Drugs for hypertension that increase gK, ATP (promote relaxation)
Minoxidil
Penacidil
Cromakalim
What does PKA phosphorylation do?
Phosphorylated phospholamban can’t bind SERCA, so SERCA active and more Ca2+ pumped into SR
Phosphorylated gK, ATP channels more likely to be open, hyperpolarization of cell causes relaxation
Phosphorylated MLCK can’t bind calmodulin, so myosin light chain can’t be phosphorylated, so can’t bind actin, which causes relaxation
Which receptors activate PKA? (and thus produce vasodilation)
Beta2 stimulated by epinephrine (in arterioles of skeletal muscle, myocardium, liver)
Alpha2 receptor by adenosine (in arterioles of myocardium, a little in skeletal muscle)
H2 receptor by histamine (in arterioles)
How is PKG activated?
NO produced in vascular endothelial cells –> NO diffuses across cell membrane and binds and activates soluble guanylate cyclase (sGC) –> sGC produces cGMP –> cGMP activates PKG
What does PKG phosphorylation do?
Phosphorylated phospholamban can’t bind SERCA, so SERCA active and more Ca2+ pumped into SR
Phosphorylated gK, ATP channels more likely to be open, hyperpolarization of cell causes relaxation
Phosphorylated MLCP inactivates myosin light chain and produces relaxation
What stimulates production of NO?
Physical deformation of endothelium (trauma, burn, bites)
Ach
ATP
Atrial naturetic factor (ANF, ANP?)
Secreted by cardiac atria in response to right atrial stretch –> ANF binds G protein type receptor NPR-A –> cGMP produced –> activates PKG
Do vascular smooth muscle cells have voltage-gated Na+ channels?
No!!!
What is a stretch-sensitive Ca2+ channel?
In the sarcolemma, and when sarcolemma (cell membrane) stretched, this stretch-sensitive Ca2+ channel opens and lets Ca2+ in. So pressure increases and muscle contracts
Do vascular smooth muscle cells have vagus stimulation?
No, VSM cells only have sympathetic stimulation
Do VSM cells have troponin?
No troponin, but do have tropomyosin, little titin, and more collagen and elastin
Do VSM cells have T tubules?
No, VSM cells don’t have T tubules, but have invaginations called caveolae which interact with the SR
Two types of innervation of smooth muscle
Multi unit: each cell separately activated by associated nerve varicosity; dependent on innervation for regulation; don’t require action potentials to contract; in most VSM cells, large arteries, veins, sphincters don’t produce APs
Single unit: phasic; have some rhythmic behavior; have extensive electrical communication via gap junctions; depol one then you depol the others; hepatic portal vein, arterioles
Many smooth musclses fall in between these categories
What does relaxed VSM look like?
Myosin light chain (wrapped around lever arm) is not phosphorylated
Cross bridge head bound to catalytic center of other cross bridge which is bound to S2 coil
Myosin jaws closed (so can’t bind actin)
What triggers VSM contraction?
MLC is phosphorylated at serine 23 –> cross bridge heads detach from each other and S2 coil –> myosin binds actin –> ATP to ADP produces force and shortening
This happens at a slow rate compared to other contractions
How does Ca2+ enter the VSM cytosol
Weird!!
Sympathetic fibers on blood vessels spill NE right onto the vessel –> NE binds alpha/beta receptors on smooth muscle cell surface –> trigger intracellular cascades
Also can be triggered by depolarizaion????
