Block 2 Flashcards
(167 cards)
1
Q
What is titin and what is its function?
A
Elastic protein to keep myosin filaments centered during contraction. Can be used as a molecular ruler during embryonic development.
2
Q
Where does titin connect in muscle?
A
2 titin filaments run alongside thick myosin filament and anchor to Z disc
3
Q
Passive length tension
A
If a muscle is pulled too far, titin and other ECM proteins produce passive force to pull it back.
4
Q
What proteins take place in the passive length tension in skeletal muscle and cardiac muscle?
A
Titin + collagen
5
Q
What proteins take place in passive length tension in smooth muscle?
A
Titin + collagen + elastin
6
Q
How does the length of titin in cardiac muscle compare to skeletal muscle?
A
Shorter titin in cardiac muscle = stiffer muscle and more force generated by titin
7
Q
Where is nebulin found and what is its function?
A
Surrounds actin thin filaments in skeletal muscle only and anchors it to Z disk. Can be used as a molecular ruler of actin.
8
Q
Alpha-actinin
A
Z disk protein that is the attachment site for actin filaments
9
Q
Dystrophin + dystrophin=glycoprotein complex
A
Focal contact proteins that link the sarcomere to the membrane and ECM
10
Q
What type of myosin is conventional or found in muscle?
A
Myosin type II
11
Q
What is the structure of myosin in muscle?
A
Hexameric protein w/ 2 heavy and 2 light chains
12
Q
Can the heavy chain bind both actin and ATP at the same time?
A
NO. ATP binding causes a dissociation of actin from myosin
13
Q
When is myosin in its bent conformation?
A
When ADP + Pi are bound
14
Q
When is myosin in its straight conformation?
A
When ADP only is bound
15
Q
What is the role of troponin T?
A
Binds tropomyosin and positions it on actin
16
Q
What is the role of troponin I
A
Inhibitory troponin that prevents myosin from accessing actin.
17
Q
What is the role of troponin C?
A
Binds calcium, which causes a conformational change to disrupt ThI and allows phosphate dissociation from myosin and the power stroke.
18
Q
At low levels of calcium, what causes the inability of the muscle to contract?
A
Steric hinderance due to troponin/ tropomyosin complex that inhibits phosphate from dissociating with myosin
19
Q
What is the length tension relationship?
A
Relative force a fiber can produce at a certain length
20
Q
What happens to the length tension relationship if a muscle is too long?
A
There are not enough fibers to cross bridge and there is less force/ tension generated
21
Q
What happens to the length tension relationship if a muscle is too short?
A
Thick filaments and Z disks collide= less force generated
22
Q
What is the optimal length for the length tension relationship?
A
2-2.25 um
23
Q
What are the steps to striated muscle contraction?
A
- ATP rapidly binds to actomyosin disrupting the bond. 2. Myosin hydrolyzes ATP to ADP+Pi rapidly 3. Myosin ADP+Pi binds weakly to actin 4. Pi dissociation due to calcium causes myosin conformational change and power stroke 5. ADP dissociation and actin/ myosin tightly bind
24
Q
What protein aids myosin in the hydrolysis of ATP to ADP+ Pi?
A
Actin helps myosin hydrolyze ATP 100x faster than myosin alone
25
Which step of muscle contraction is the limiting factor in force generated/ rate of contraction?
ADP dissociation from actin/ myosin
26
What are slow twitch type I skeletal muscle fibers?
Small, fatigue resistant, red myoglobin, oxidative metabolism with increased mitochondria and decreased glucose. (Back muscles)
27
What are fast twitch type IIa skeletal muscle fibers?
Fatigue resistant, red myoglobin, oxidative metabolism, increased mitochondria & glycogen
28
What are fast twitch type IIb skeletal muscle fiber?
Fatigable, large white myoglobin, glycolytic metabolism, decreased mitochondria and increased glycogen
29
What step in the excitation of skeletal muscle causes calcium influx and neurotransmitter release?
NMJ membrane depolarization
30
What effect does acetylcholine have on the post synaptic membrane?
Causes transient depolarization or end plate potentials
31
What does the action potential in muscles do?
Travels down the T tubule and activates voltage-gated DHP receptors physically linked to Ryr receptors in sarcoplasmic reticulum for calcium release.
32
What type of Ryr receptor does cardiac muscle have?
Calcium-induced calcium receptor
33
How does norepinephrine regulate cardiac muscle?
Overall, it increases heart rate (chronotrophy), contractility (inotrophy), and relaxation rate (lusitrophy) = rapid contraction with lots of force
34
What does norpinephrine do at the molecular level?
Binds to beta adernergic receptors and increses calcium influx by phosphorylation of calcium channels
35
What is one reason calcium levels are highly regulated in cardiac muscle?
So twitch force can increase or decrease
36
What types of contractions do smooth muscles have?
Slow, continuous contractions that are involuntarily controlled
37
What factors influence smooth muscle contraction?
Autonomics, hormones, chemicals, pacemakers
38
True or false: smooth muscle generates less force than skeletal muscle?
FALSE. Smooth muscle generates more force than skeletal muscle because it has more cross links
39
What is the latch state present in smooth muscle?
When ADP remains bound to actomyosin
40
What type of calcium receptor is present in smooth muscle?
Calcium-induced calcium release
41
What role does calmodulin have in smooth muscle thick filament regulation?
Bound by calcium and activates myosin light chain kinase (MLCK)
42
What role does myosin light chain kinase (MLCK) have in thick filament regulation of smooth muscle?
MLCK phosphorylates myosin light chain so it can interact with actin (phosphorylation = activation)
43
What function does ROK have in smooth muscle thick filament regulation?
ROK inhibits myosin light chain phosphatase (MLCP)
44
What is the function of myosin light chain phosphatase in smooth muscle thick filament regulation?
MLCP dephosphorylates the myosin light chain to return it to an inactive state.
45
How is tonically active smooth muscle created?
Myosin light chains are phosphorylated and remain phosphorylated for awhile to form cross-bridges and tonically active muscle
46
Is calcium required for ROK to produce contraction?
NO
47
What is the role of caldesmon/ calponin in smooth muscle regulation?
Take part in thin filament regulation by binding thin filaments. They are inhibited by phosphorylation
48
Muscular dysrophyies
Lacking/ mutated focal proteins. Contractions cause tears in muscles and membranes, altered ion flux, and cellular degeneration
49
Familial Hypertrophic Cardiomyopathy
Leading cause of sudden cardiac death. Usually due to single amino acid mutation in cardiac heavy chain that changes ATP hydrolysis. This causes decreased force production and ventricular wall hypertrophy.
50
Malignant hyperthermia
Myopathy due to skeletal muscle Ryr defect. Triggered by anesthetics and causes uncontrolled skeletal muscle contraction and hyperthermia.
51
Cardiac hypertrophy and failure
Decrease in cardiac muscle Ryr receptors (Ryr-2)
52
How does viagra function in smooth muscle?
Inhibits cGMP breakdown by blocking PDE5. Inhibits smooth muscle contraction to promote relaxation of blood vessels to achieve erection.
53
What is endocrine signaling?
Source of signal is distant from the target and signals are transmitted in the blood stream
54
What is an example of endocrine signaling?
Insulin is secreted by beta islet cells in the pancreas and has far reaching effects on adipose tissue, the liver, and skeletal muscle
55
What is a treatment for type I diabetes and what type of signaling does it take advantage of?
Exogenous insulin is delivered to the blood stream because insulin signaling is an example of endocrine signaling.
56
What is paracrine signaling?
A localized signaling mechanism where a signal diffuses out of the source cell and effects cells in the immediate vacinity
57
Secretion by vascular endothelial cells is an example of what kind of cell-cell communication?
The secretion of factors by vascular endothelial cells is an example of paracrine signaling. The goal of the paracrine signals is to maintain balance in cardiac output and other cardiac factors.
58
What happens if there is a dysfunction in vascular endothelial cells?
Dysfunctional paracrine signaling from vascular endothelial precursor cells can cause cardiovascular disease.
59
What is an example of paracrine signaling in tumors?
Tumors secrete paracrine angiogenic factors to stimulate angiogenesis and blod flow to the tumor
60
What is juxtacrine signaling?
Signaling to an immediate neighbor where the source cell has a ligand and the target cell has a receptor.
61
What is an example of juxtacrine signaling in the nervous system?
Crawling axons in development encounter permissive and restrictive ligands that either signal the axon to stop or to keep growing.
62
What is autocrine signaling?
Self-stimulation in a cell
63
How is VEGF in epithelial tumors an example of autocrine signaling?
EGF binds to EGFR on epithelial cells. EGF stimulates the production of VEGF, which diffuses out of the cell then binds on the cell's own VEGF receptors.
64
What is intracrine signaling?
Signal generated inside of the cell DOESN'T leave and stimulates intracellular receptors
65
How is estrogen an example of intracrine signaling?
Estrogen diffuses into the cell and is metabolized. The metabolized product binds estrogen receptors within the cell.
66
What is the definition of signal transduction and where is there amplification in the pathway?
Signal transduction is the conversion of a signal to a functional change within a cell. There is amplification between the reception of the signal and the transduction.
67
What type of receptor is the GABA receptor and what is its function?
GABA is a inhibitory neurotransmitter in the CNS. It binds and opens chloride channels to let chloride into the cell and effectively hyperpolarizes and inhibits transmission of signals.
68
How are ligand-gated ion channel signals terminated?
Receptor inactivation; Ion channel inactivation (think sodium channel inactivation); Membrane transporters (remove ions)
69
How do G-protein coupled receptors transmit signals?
Bind extracellular signals and receptor undergoes conformational change to activate g-proteins. G-proteins have gtpase activity and can interact with effectors to cause changes in cellular function
70
How are g-proteins inactivated?
Hydrolysis of GTP
71
What are the steps of the G stimulatory pathway?
1. Epinephrine binds Beta-adernergic receptors to acitvate. 2. Receptor activates G-proteins (amplification) 3. G-proteins activate adenylyl cyclase (amplification) 4. Adenylyl cylase synthesizes cAMP (amplification) 5. cAMP activates protein kinase a (PKA)
72
How does adenylate cylcase work?
It catalyzes conversion of ATP to cAMP and pyrophosphate
73
How is PKA activated?
cAMP binds regulatory subunits so they dissociate
74
What is the function of PKA?
It is a protein kinase that phosphorylates serine and threonine residues
75
How is the Gs signal pathway terminated?
Receptor inactivation G protein inactivation (hydrolysis) Phosphodiesterase degrades cAMP Dephosphorylation of proteins
76
What is the function of phosphodiesterase?
Degrades cAMP
77
What are the steps to the Gq signaling pathway?
1. norepi binds to Alpha-adernergic receptors 2. Activated receptor activates G proteins 3. G-proteins activate phospholipase C 4. Phospholipase C creates IP3 and DAG 5. IP3 binds to IP3 Receptors on ER and stimulates calcium release 6. DAG activates protein kinase C
78
How is the Gq signaling pathway terminated?
Receptor inactivation G protein inactivation (hydrolysis) IP3 and DAG degraded Phosphatase dephosphorylation of proteins SERCA pumps calcium back into ER
79
How does cholera affect the cell?
Targets Gs g-proteins and constitutively activates adenylyl cylcase to increase cAMP and have sustained activation of PKA
80
What is overall affect of Gi signaling in the cell?
Gi inhibits adenylyl cylase and decreases levels of cAMP
81
How does pertussis affect the cell?
Targets Gi g-proteins and inhibits them. Causes net activation of adenylyl cylccase and increased cAMP and activated PKA
82
What is nuclear receptor/ intracellular signaling?
Receptors are inside the cell and signals are either intracellular or able to pass thru lipid membrane.
83
How are steroid hormones examples of nuclear receptors?
Steroid hormones can diffuse into the cell and bind to receptors to activate them within the cytosol. Hormone + receptor are transcription factors that enter the nucleus and alter gene expression.
84
What type of signaling is tamoxifen an example of?
Nuclear receptor/ intracellular signaling
85
How does tamoxifen work?
Tamoxifen is an estrogen mimic. In breast cancer, estrogen promotes the proliferation of cancer cells, so tamoxifen binds to the estrogen receptor to block its conformational change and interaction with coactivators.
86
What are the two forms of guanylate cyclase receptors
rGC in plasma membrane that responds to extracellular ligands. sGC in cytosol that responds to intracellular signals like NO from neurons or endothelial cells
87
What is the function of guanylate cyclase?
Change GTP to cGMP
88
What does cGMP activate?
cGMP channels, cGMP binding proteins, Protein kinase G
89
What is the function of PDES?
=phosphodiesterase. Catalyzes hydrolysis of cGMP to GMP
90
What are the Nodes of Ranvier
~1 mm gaps between myelin sheaths
91
What two reactions can result after NT reception?
1. membrane depolarization and excitatory post synaptic potentials (EPSP) 2. membrane hyperpolarization and inhibitory post synaptic potentials (IPSP)
92
What does the magnitude of post synaptic potentials depend on?
Amount of NT released (graded)
93
In general, is the NT release from one excitatory neuron enough to trigger an action potential?
NO (but that's not true for skeletal muscle NMJ)
94
What is the length constant?
A constant used to determine how far a graded potential will go via passive electrical conduction before degrading. Property of the neuron.
95
What is cellular integration?
Process of a neuron integrating inhibitory and excitatory signals in determining whether or not to fire and action potential. This is a continuous process in neurons
96
What is temporal summation?
Summation of neuronal signals from multiple neurons
97
What is spatial summation?
Summation of neuronal signals from ONE neuron
98
What does the conduction equation for neurons dependent on?
Distance from origin of signal and the length constant of the cell. The conduction equation shows exponential decay.
99
What is conduction velocity related to?
Membrane resistance (presence of myelin) and cable diameter (bigger diameter = faster velocity)
100
What is the typical range for conduction velocity for mammals?
0.25 to 80 m/s
101
What is the function of myelin?
Covers/insulates sodium and potassium channels except at the Nodes of Ranvier so APs have to jump between nodes instead of activating every channel. Increases conduction velocity.
102
What are the causes and effects of Multiple Sclerosis?
Inflammatory autoimmune disease that damages myelin. Damage causes decreased conduction velocity, frequency related block of conduction, or total block. Can cause ectopic impulse generation, increased mechanosensitivity, and crosstalk between demyelinated neurons.
103
What is one treatment for multiple sclerosis and how does it work?
Potassium channel blockers. Normally extracellular potassium causes decreased action potential duration. Potassium channel blockers reverse this effect to prolong action potentials.
104
How do local anesthetics work?
Temporarily inactivate sodium channels
105
What are the stages of NT release?
Sythesis, storage, release, receptor activation, inactivation, reuptake, and degredation
106
Where do motor neurons receive inputs from?
Excitatory and inhibitory synaptic inputs from sensory afferents and from supraspinal synapses directly or from interneurons
107
What happens to ACh shortly after it activates the nicotinic ACh receptors?
It is rapidly diffused or degraded by acetylcholine esterase to prevent multiple reactivations of ACh receptors.
108
What type of channel is the nicotinic ACh receptor?
Ligand gated sodium channel
109
What is the function of choline acetyl transferase (CAT)?
Synthesizes ACh
110
What is the function of vesicular ACh transporters?
Pump ACh against gradient into vesicles by exchanging with hydrogen. (There are hydrogen pumps to restore acidic pH to vesicle)
111
What is the function of post-junctional folds in musclular cells?
Have high concentrations of acetylcholine receptors to bind a lot of ACh. Also have VG sodium channels to propagate the generated AP efficiently.
112
What is the active zone in motor neurons?
Site where vesicles with ACh are lined up with post synaptic receptors to ensure efficiency of NT release.
113
What is special about end plate potentials in skeletal muscle?
The lining up of the active zone and post junctional folds and the release of ~200 vesicles produces a depolarization of ~40 mV that WILL fire an action potential.
114
How are signals terminated in skeletal muscle?
Repolarization of T-tubule membrane brings DHP to closed configuration and therefore closes Ryr. SERCA pumps calcium back into SR and terminates signal.
115
What causes Myasthenia gravis?
Patients have antibodies agains AChR. This causes muscle weakness because neurons can't stimulate the muscle cells.
116
What is one treatment for myasthenia gravis?
Inhibition of acetylcholine esterase to increase the concentration of ACh to stimulate available, functioning nicotinic ACh receptors
117
What are the two types of smooth muscle?
1. mutliunit: independently control each cell. 2. unitary: muscle cells linked by gap junctions and function as one
118
Where does calcium come from in smooth muscle?
Outside the cell and from the SR
119
How is calcium regulated in smooth muscle?
Gq/ IP3 pathway, VG calcium channels, and stretch-activated calcium channels
120
Do smooth muscles ahve neuromuscular junctions?
NO. Autonomics have multiple diffuse junctions
121
What are varicosities?
Sites of NT release in smooth muscle
122
Do motor neurons innervate smooth muscle?
NO
123
What are the two NT and their receptors in smooth muscle?
1. ACh and muscarininc G protein receptors 2. Norepinephrine and B adernergic/ Gs receptors
124
What is the function of ACh and muscarining G protein receptors in smooth muscle?
ACh is from parasympathetic nerves and stimulates the Gq signaling pathway to promote calcium release
125
What is the function of norepinephrine and B-adernergic/ Gs receptors in smooth muscle?
Receptor activation activates adenylyl cyclase and increases levels of cAMP. cAMP inhibits MLCK and inhibits contraction
126
What does the Gi pathway do overall in smooth muscle?
Inhibition of adenylyl cylcase causes decreased cAMP and promotes contraction because MLCK is NOT inhibited
127
What is an example of endocrine regulation of smooth muscle?
Oxytocin synthesized in the pituitary gland stimulates uterine smooth muscle to contract
128
What is an example of paracrine regulation of smooth muscle?
Endothelial cells stimulated by calcium induce eNOS to synthesize NO. NO enters smooth muscle cells and binds soluble Guanylyl cyclase to activate cGMP. Used to regulate blood pressure.
129
How does cGMP affect smooth muscle cells?
Activates PKG that inhibits calcium channels and inhibits contraction of smooth muscle.
130
Do pacemaker cells in smooth muscle require input?
NO. They are spontaneously active.
131
What is unique about Rho-kinase in smooth muscle?
It can change contractile activity WITHOUT calcium
132
How does Rho-kinase change contractile activity without calcium stimulation?
Ligand activates receptor to activate Rho-GTPase. Rho-GTPase activates Rho-kinase that phosphorylates MLC to activate.
133
What is the RMP of smooth muscle and what is a key determinant of RMP?
-50 to -60 mV. Regulated by potassium channels
134
What types of signals stimulate SM?
Action potentials and graded depolarizations
135
What are the levels of VG sodium and calcium channels in smooth muscle?
LOW levels of VG Na+ channels and MANY VG Calcium channels
136
What kinds of factors govern GI smooth muscle?
Hormones in blood stream, stretch receptors, autonomic and enteric neurons, macrophages (release NO)
137
What factors cause AP firing in cardiac muscle cells?
ONLY signals from cardiac pacemakers
138
What causes the plateau phase in cardiac action potentials?
Calcium influx balances the potassium efflux
139
What controls the length of contraction in cardiac muscle?
SERCA pumps
140
What effect do beta adernergic and Gs proteins have on cardiac cells?
G proteins can decrease calcium by stimulating calcium pumps
141
What is rigor mortis?
Myosin in muscles is tightly bound to actin and there's no ATP present, so you get rigid muscles
142
How are muscles adapted to contract at different speeds?
By controlling the rate of phosphate and ADP dissociation mainly. And by the rate of metabolism (fast, oxidative vs. slow)
143
What is the function of troponin T?
Links the troponin complex to the tropomyosin on actin
144
Does cardiac muscle have tropomyosin?
Yes. Both skeletal and cardiac muscle use troponin/ tropomyosin to regulate contraction.
145
What is the difference between skeletal and smooth muscle regulation? (thin vs. thick filament)
Skeletal muscle is mostly thin filament regulation (troponin/tropomyosin) while smooth muscle is mostly thick filament regulation (MLCK and MLCP)
146
What is one similarity between unitary smooth muscles and cardiac muscle?
Both can have high degrees of electrical coupling
147
What causes smooth muscle to have longer durations of muscle contraction and greater force generation?
The slower cycling of myosin cross bridges and the greater amount of cross bridges formed
148
What does sympathetic epinephrine do overall to cardiac muscle?
"Turns up the volume" and causes greater calcium release for shorter periods of time
149
What does cGMP do in smooth muscle?
Promotes MLCP to activate dephosphorylation of myosin light chains so they inhibit contraction (think Viagra)
150
Why is relaxed muscle extensible?
Because myosin in smooth muscle is either bound to actin or ATP, so its not all or one and has some give when bound to ATP.
151
What is a dense body?
Similar to Z-discs in smooth muscle with lots of alpha-actinin
152
In which stages of muscle contraction are there weak bonds ?
When ATP is bound to myosin; Right when myosin-ADP-Pi bind to actin (rapid equilibrium between bound and not)
153
In which stages of muscle contraction are there strong bonds?
Pi dissociation from actinomyosin+ADP; ADP dissociation from actinomyosin (rigor)
154
What are the three filaments in a sarcomere?
Thick, thin, and titin
155
What is the function of alpha-actinin?
Runs the length of the z-disc and attaches actin to z-disk
156
What is the structure of myosin II?
Hexamer with two heavy chains and 2 pairs of light chains. There is a regulatory light chain and an essential light chain
157
What is caldesmon/ calponin?
Thin filament regulation in smooth muscle. They act like troponin in smooth muscle. If they are phosphorylated, the thin filaments are ON and can interact with thick filaments.
158
Which ligands are used for nuclear receptors?
Retinoic acid, Vitamin D, steroids, and thyroid hormone
159
What effect does myelin have on Rm or membrane resistance?
It increases the membrane resistance. Increases the resistance to leakiness
160
What drugs target the GABA receptors?
Propofol, benzos, volatile anesthetics, ethanol
161
Which NTs use monoamine receptors?
Norepinephrine, dopamine, serotonin
162
What is the function of an SSRI?
Inactivates serotonin reuptake channels to increase serotonin in the synaptic cleft
163
Where is acetylcholinesterase housed in the synaptic cleft?
Basal laminae
164
What is the MOA of botulinum and tetanus?
Inhibits ACh release
165
What is the MOA of poison darts?
Inhibits ACh receptor
166
What does depohsphorylated phospholamban do?
Interacts with SERCA to inhibit it. Without phosphorylation, it doesn't interact with SERCA.
167
What is a myofibril vs a myofilament?
A myofibril is a bundle of myofilaments.
A myofilament is a bundle of three filaments (actin, myosin, and titin) that make up linear arrangements of sarcomeres
