Muscles Flashcards
1
Q
What makes up a motor unit
A
The presynaptic neutron and collection of muscle fibres which it innervates
2
Q
What is the diameter of a muscle fibre generally
A
1-2 micrometer
3
Q
How wide is a synaptic cleft
A
50-70 nm
4
Q
What opens when an AP arrives at a presynaptic terminal?
What does this result in?
A
The motor axon opens voltage gates Ca channels
Causes vesicles to fuse with plasma membrane, releasing their contents into the cleft
5
Q
How has vesicles fusion bee visualised
A
Using rapid freezing of the muscle during neuromuscular transmission followed by freeze fracture EM
6
Q
What is the conc of ACh in vesicles
A
100-200mM
Roughly 10^4 molecules/vesicle
7
Q
What is the is the release of ACh vesicles proportional to?
A
[Ca2+]^4
8
Q
What is the mean synaptic delay?
Where does most of the delay occur?
A
1ms
Within the presynaptic terminal
9
Q
What is the timing of ACh diffusion and post synaptic response
A
Diffusion: 10 microseconds
Response: <100 microseconds
10
Q
ACh is an anion
True or false
A
False
It is a cation
11
Q
What forms ACh
A
Choline and acetyl CoA by the enzyme choline acetyltransferase
12
Q
What happens to ACh chemically when it is released?
What does it yield
A
It is hydrolysed by ACh-ase
Acetic acid and choline
13
Q
How many subunits does a AChR channel have
How are they structured
A
5
The hydrophilic, negative side chains point inwards creating a selectivity filter which rejects anions but accepts Monovalent cations
Lipophilic point out into lipid bilayer, stabilising the pentamer
The alpha subunits each contain an extra cellular binding site for ACh
14
Q
How was the current through a single AChR investigated?
A
Neher and Sakmann (and others) used a patch clamp
15
Q
How long do AChR open for
What experiment was done to show this
A
<1ms
Bathed in a maintained concentration of ACh - opened in random durations
16
Q
What is required for an AChR to open
Why is this
A
2 ACh molecules must bind to both alpha subunits
Suppressed responses to small quantities of ACh but produces a sharp response to higher concentrations
17
Q
Should you still reread the handouts despite learning these flash cards
A
Absolutely. I have skipped entire paragraphs that Michaelmas term Joe thinks irrelevant but may later be important
18
Q
What dictates the decay time of an end plate potential
A
Fibre diameter: the larger the fibre, the faster the decay
19
Q
What is the reversal potential for the ESPC
A
0mV
20
Q
Is the AChR exclusively a sodium Channel
A
No
It is a monovalent cation channel permeable to both K and Na
It is also slightly permeable to Ca
21
Q
Do ESPCs speed up with depolarisation
Why does this occur
A
Yes due to some voltage dependence of AChR gating
It is energy efficient: if the membrane is already depolarised, the conductance switches off faster when it is no longer needed to produce depolarisation
22
Q
What is the active ingredient in curare
A
D-tubocurarine
23
Q
Why is curare toxic
A
D-tubocurarine competes with ACh for binding on AChR without opening the channel
This reduces the post synaptic response leading to separation of EPP and AP
24
Q
How can the amount of ACh releases in the cleft be studied
A
Eserine blocks ACh-ase
25
What effect does eserine have
Prolongs EPSP and EPSCs
26
State nicotine’s relation to ACh
Agonist
It acts specifically on ion channel ACh receptors without activating muscarinic ACh receptors which mediate slow responses in other types of cell
27
How is snake venom deadly
Contains α-Bungarotoxin which binds tightly and blocks AChRs
28
How are black widows deadly
Their venom contains alpha-latrotoxin which produces a release of the pool of available presynaptic transmitter, resulting in a block from ACh depletion
29
How is Botulinum toxin toxic
Prevents release of ACh
30
What is a muscle fibre
How do they connect to bone
A multinucleate cell with a diameter between 50-150 microns
They are continuous with connective muscle tissue tendons which connect to bone
31
What structures directly reflect a contractile function
Myofibrils (made of contractile proteins that run along the fibre axis and are between 1-2 microns in diameter)
32
Are T tubules continuous with extra Elul are fluid?
Yep
33
What is the sarcoplasmic reticulum
An intracellular membrane network isolated from the extra cellular space which stores Ca ions
34
What muscles are striated
Cardiac and skeletal
35
In striation what is dark and what is light
Dark - A band containing thick filaments mainly containing myosin
Light - I band with only thin filaments, containing actin, troponin, and tropomyosin
36
Where is the Z band
In the centre of the I bands and provide attachment sites
| The Z to Z units of myofibril form the sarcomere
37
Structure of myosin
1.6micrometers in length
| Consists of a tail of 2 long light meromyosin strands twisted together which are both connected to globular heads
38
What does myosin bind to and what does this trigger
Actin
| ATPase activity in the S1 fraction
39
When is the reaction between the myosin and actin permitted
If the tropomyosin molecule is moved deeper into the groove that is formed by the thin filaments caused when Ca binds to the troponin
40
Generally what does a cross bridge cycle do
Pulls the thin filaments towards the centre of the sarcomere
41
What produces sarcomere shortening
The relative sliding of the interdigitated thick and thin filaments
42
What does increasing myofilament overlap do?
Increases force generation
43
Why is there a constant isometric force at sarcomere lengths below 2.2 to 2.0 microns?
The middle of the thick filament lacks myosin heads, restricting opportunities for cross bridge formation, which shortens filament overlap
44
What does excessive myofilament overlap result in
What does this do
Thin filaments collide with one another
OR
thick filaments colliding with the Z lines
Diminish force production
45
How are cross bridges broken
A process that requires hydrolysis of ATP
this thus allows further cross bridge formation
46
What is rigor Mortis
A progressive recruitment of cross bridges that fail to dissociate
47
What 2 factors affect production of force from cross bridge cycles
Number of interacting sites
| Force generated by each site
48
Why do muscles usually act at a disadvantage
What does this mean
The perpendicular distance from the line of action of the muscle to the joint is normally considerably smaller than the distance of the load to the joint
49
What does repetitive activation of of a muscle result in
What about for higher stimulation frequencies
A sequence of twitches with no increase in peak tensions
Muscles may be reactivated befor the previous twitch has fully recovered to result in a twitch that rises above that of a single twitch
50
What happens during tetanus
High activation frequencies results in tensions summing
51
Describe the length tension relationship
Gradual increase in tension with small degrees of stretch but beyond a certain degree of elongation there is a significantly non linear increase in tension.
After a certain length, tension decreases as length increases
52
Why does tension eventually decreases as length increases
Thick filaments fail to overlap so active tension cannot be developed
53
Equation for force velocity relationship
(F+a)(v+b)=(Fmax + a)b
54
What are smooth muscles
What is the load they work against
Muscles that line walls of hollow organs
The pressure within the tube
55
Shape of smooth muscle
Elongated and spindle shaped
NOT striated (no sarcomere)
Thick and thin are NOT transversely aligned but attached in dense bodies in the cytoplasm and to attachment plaques at the membrane
No T Tubules
56
What systems control smooth muscle
Autonomic (both para and sympathetic) and hormonal
| Can generate active tension without nerve activity - nerves often modulate
57
What does caldesmon do
Binds to actin-tropomyosin to inhibit cross bridge cycling
Ca causes caldesmon to dissociate from actin by binding to the regulatory calcium binding protein calmodulin
58
How does PKC cause dissociation
Phosphorylates caldesmon
59
What does binding of Ca to myosin might chain do
Increases cross bridge formation
60
Role of myosin light chain kinase
What is this process called
Phosphorylation of myosin light chain causing increased cross bridge cycling which lasts until dephosphorylation by myosin phosphatase
Covalent regulation (covalent bind formed)
61
What happens if the cross bridge is dephosphorylated
Can maintain tension without cycling or ATP consumption
| Hence why smooth muscle is >300x more efficient than skeletal in maintained contraction
62
What happens when the gut is stretched
Stretch activated ion channels lead to mechanically induced depolarisation and contract.
This assisted peristalsis
63
Where does an action potential travel in muscles
Over surface membrane and T tubule which triggers release of intracellularly stored Ca from SR
64
What is an inward rectifier and what do it do
A channel that Allows K to pass more easily into than out of a cell, minimising leaks and the amount of inward current required for the plateau
65
What are Ca channels responsible for in muscle
Plateau phase
66
What does the ryanodine receptor do
Acts as a calcium channel in SR
67
How many axon branches innervate a muscle fibre
Where do they attach on the muscle fibre
Each branch attaches to a single muscle fibre to form a motor end plate
The centre
68
How big are muscle fibres
1-2μm in diameter
69
How frequent are junction folds
Every 1-2μm
70
What are muscular active zones
Specialised thickenings immediately above the junction fold in the Presynaptic axon membrane
71
How big are the vesicles in muscle
Where are they found
50nm in diameter
Clustered around the active zone
72
What is in the synaptic cleft
Mucopolysaccharide glue
73
What is the basal lamina
A layer of extracellular material visible in EM
74
What happens as the AP reaches the motor axon
VG Ca channels open in the presynaptic terminal. This rise in [Ca] causes vesicles to fuse with the plasma membrane releasing their contents
75
What is the minimum synaptic delay in a frog at 17 degrees C
What is the mean
500μs
1ms
76
Where does most of the synaptic delay occur
How fast does ACh diffuse across the cleft and how fast is the response
In the presynaptic terminal
In about 10μs
<100μs
77
How is ACh synthesised
What happens after release
From choline and acetyl CoA
By choline acetyltransferase
It is rapidly hydrolysed by AChase which is localised to the basal lamina
78
What are the products of ACh hydrolysis
Acetic acid and choline
79
What is the structure of an AChR
4 types of gylcoprotein subunit (α,β,γ,δ) but 5 subunits total arranged ααβγδ
Hydrophilic negative side chains point into the pore creating a selectivity filter which rejects anions
The lipophilic side chains point out and stabilise the pentamer
Each α subunit contains an ACh binding site on the extracellular domain
80
What was the conductance of a single AChR
30pS or 30/Ω
81
What happens if AChRs are bathed in ACh
Openings are short <1ms and random in duration
| Openings tend to be clustered into bursts with long intervals
82
What happens after a long period of maintained [ACh]?
Why does this happen?
The AChR stops opening or is desensitised
Protective mechanism in the case that limits the dissipation of the ion gradient in the event of catastrophic release of transmitter
83
How did Katz eliminate the AP
By partially blocking synaptic transmission with curare
84
What is an EPP
A residual subthreshold potential which rise every few miliseconds then decay (the larger the fibre diameter the larger the decay)
85
Why are EPSPs slower than EPSCs
The time taken to charge and discharge the membrane capacitance
86
What happens to the EPSC at more and more depolarised holding potentials
EPSC gets smaller and disappears at 0mV then gets larger again in the opposite direction
87
How do we know the AChR is simply a monovalent cation channel
The current varies linearly so the summed current varies linearly and the reversible potential is near 0mV
88
Do ESPCs change speed with depolarisation
How is this beneficial
Yes they speed up due to some voltage dependance of the AChR
Saves energy: if the membrane is already depolarised the conductance switches off faster when it is no longer needed to produce depolarisation
89
What does Eserine do
What is it also called
Why is it useful
Blocks AChase
Physostigmine
Measurement of how much ACh is released
90
What is nicotine in muscles
An agonist for AChRs
Works specifically on ion channels receptors without activating muscarinic AChRs which mediate slow responses in other cells
91
What does snake venom contain
Why are they bad
How have they been used
α-bungarotoxin
Blocks AChRs
Radioactive ones have been used to count the number of AChRs in a NMJ
92
How does black widow venom work
Produces a massive release of ACh in pre synaptic terminal depleting ACh stores
93
What does botulinum A do
Acts as an enzyme, cleaving SNAP 25 to prevent vesicle fusion with the presynaptic terminal, resulting in paralysis of the muscle.
94
How is the frequency of MEPPs affected as observed by Fatt and Katz
Decreased by decreasing external Ca or increasing Mg
It was increased by increasing external [K+] or osmotic pressure
These allow affect the release of vesicles
95
What did Katz suggest about vesicle release
1 quantum = release of 1 vesicle
Release is probabilistic: the great increase in release during an EPP would correspond to a transient increase in probability of release for the vesicle population
96
How should EPSPs fluctuate
Probabilistically in size but be comprised of single integral numbers of quanta
97
How to find probability of a peak
The area of the peak
98
Pk =?
(e^-m) x (m^k)/k!
99
What is m in the Poisson equation
Mean number of quanta released
| ie quantal content
100
What can be seen if the AP is recorded near the end plate
The upstroke also shows the initial EPP as the membrane charges up to the threshold
101
What can you see of EPPs when curare is added to the end plate
What does this mean
EPPs are subthreshold and the peak size is seen to decay exponentially with distance from the end plate
The region over which a pre synaptically evoked muscle AP is limited to the area near the end plate
102
Discuss the uses of Botulinum A
By preventing ACh release it can be used to relax the muscles causing wrinkles in cosmetics.
However it is also the most lethal toxin known to man, causing widespread paralysis
103
Describe the action of α latrotoxin
forms pores to allow Ca entry resulting in vesicle release and initial stimulation, followed by depletion as continual release occurs
104
Can muscles depolarise in the absence of presynaptic activity
Yes - MEPP
105
At what intervals for MEPPs occur
Random intervals
106
What produces a MEPP
A quantum of about 10,000 molecules of ACh
107
Can you find depolarisation if tetrodotoxin is used to block the presynaptic APs
Yes: MEPPs occur despite this
108
What caused the frequency of MEPPs to change
Frequency decreased by a decrease in external Ca2+
Decreased with an increase in Mg
Increased by increasing external [K+] or osmotic pressure
109
What causes the frequency of MEPPs to decrease
Decreasing external calcium
Increasing external Magnesium
110
What causes the frequency of MEPPs to increase
Increasing external [K+] or osmotic pressure
111
What does a single quantum correspond with
Who showed this
A single presynaptic vesicle containing ACh
Katz et al
112
What dictates when an ACh vesicle is released
Probability
The transient increased release during an EPP is due to a transient increase in probability of release of the population of presynaptic vesicles
113
The hypothesis that quantum release is probabilistic leads to a number of predictions. Name one.
EPSPs should fluctuate probabilistically in size but be composed of integral numbers of quanta
114
How did Katz show the probabilistic nature of vesicle release
What did he see
Used low Ca2+ conditions to reduce probability of release
Distinct peaks that can be seen, reflecting the simultaneous release of 1,2,3 or 4 quanta
115
What should the area of peaks of vesicles release follow
The Poisson distribution
116
What is assumed when we say vesicle release follows the Poisson distribution
Vesicles are identical and independent
Probability of release is low
117
Give the Poisson distribution equation
Pk =?
(e^-m) x (m^k)/K!
118
In the Poisson distribution equation, what do each of the following stand for:
a) k
b) m
c) Pk
a) number of quanta
b) mean number of quanta released during an EPP
c) probability that the EPSP comprises k quanta
119
What is quanta content
Mean number of quanta released during an EPP
120
If we recorded the voltage near the end plate and an AP, what would we see?
How would it be different to if it were >5mm from the end plate
An upstroke showing the initial EPP as the membrane charges up to the AP threshold
The initial EPP disappears
121
How happens to subthreshold EPPs in a curare treated muscle
What is this due to
Peak size of EPPs decays exponentially with distance from the end plate
The cable properties of the muscle
122
What do the cable properties of the muscle mean
Without regenerative inward current through VG Na+ channels, the depolarisation fades with distance as more and more of the end plate current means out of the muscle fibre membrane
123
Why do postganglionic cells often offer dual innervation
They often have opposite actions
124
What do post ganglionic cells of the sympathetic nervous system release
What is its effect on cardiac muscle
Noradrenaline
Excitatory
125
What do post ganglionic cells release
ACh
126
What are the 4 ways skeletal muscle structure reflect their specialised function
1) myofibrils
2) internal membrane systems to regulate muscle contraction
3) specific organelles
4) abundance of myoglobin and creatine phosphate, as well as dystrophin
127
How do myofibrils directly reflect the contractile function of muscle
Made up of contractile proteins that run along the fibre axis
128
What are the 2 internal membrane systems in muscles that are specialised to regulate muscle contraction
Transverse tubules
Sarcoplasmic reticulum
129
What are transverse tubules
A fund network of tubes whose lamina are continuous with the ECF
Their extensive networks are placed regularly along the fibre length and transversely across the fibre axis
130
Describe the sarcoplasmic reticulum
What is the purpose
Forms a network of tubes and sacs whose lamina are isolated from the ECF
Intracellular storage of Ca2+
131
What organelles are particularly important in skeletal muscle cells (5)
```
Ribosomes
Lysosomes
Lipid granules
Mitochondria
Glycogen granules
```
132
Why is dystrophin important
Abnormalities in dystrophin are associated with the pathogenesis of muscle dystrophy
133
What is the A band
Anisotropic
Contains thick fibres
134
What is the I band
The lighter isotrophic band
Contains only thin fibres
135
Where are the Z lines
At the centre of the I bands
These provide attachment sites
136
What is the M line in muscle
The cross connections that alight the thick filaments
137
What forms a sarcomere
The repeating anatomical unit of a myofibril that extends from Z line to Z line
138
What are the thick proteins mostly made up of
Myosin
139
What is a myosin molecule made of
A tail of 2 long light meromyosin strands that are twisted together and each tail is connected to a globular head
The head is made of a heavy meromyosin with 2 fractions (S1 and S2)
140
How long is a myosin molecule
1.6μm
141
What are the functions of the 2 fractions of the myosin head
S1 - contains globular heads; where ATPase activity happens
S2 - contains the necks which connect the heads to the tails
The myosin heads binds to actin, which in turn triggers ATPase activity in the S1 fraction
142
What are thin filaments made of
Units of actin with troponin and tropomyosin
143
How long are thin filaments in amphibians
2.05μm
144
How long is the periodicity of a thin filament
5nm
145
How are thin filaments formed
Each actin unit is polymerised in vivo to form thin filaments
These thin filaments are organised into paired chains that are twisted around each other with a periodicity of 36.5 nm
146
Can actin bind to myosin in vitro
Yes
Actin is capable of binding with myosin in vitro and in vivo
147
Describe the structure of tropomyosin
Rod shaped about 40nm long
Forms α helical subunits that become packed into the depth of the groove formed by intertwined helical actin chains
148
How does a tropomyosin molecule compare to actin size wise
Why
One tropomyosin molecule spans 7 actin units
Prevents the binding of these actin units to myosin in resting skeletal muscles
149
Physically what must happen on a molecular level to allow actin to bind to myosin
What controls this configuration change
Only allowed if tropomyosin is moved deeper into the groove formed by thin filaments
Troponin
150
Describe the structure of troponin
Consists of 3 subunits: TnC, TnT and TnI
151
What does the TnT subunit do
It is associated with the tropomyosin ribbon at 40nm intervals
152
What happens to troponin when Ca2+ binds
Triggers a conformational changes in TnC subunit to pull tropomyosin into the actin groove
This exposes the myosin binding sites present on the actin molecule
153
What is the purpose of TnI subunit
It is uncertain
154
How does increasing filament affect force produced
Increases force generation
155
Do myofilament lengths change
No
156
Below what sarcomere lengths is isometric force constant
Why
2.2 to 2.0 microns
There are no myosin heads in the middle of the thick filaments
157
How long does a single muscle twitch last
How many twitches are produced by activation from a single nerve
>200ms
1
158
Is there a change in peak tension if there is repetitive activation of muscle at a low frequency
No it simply elicits a sequence of twitches with no increase in peak tension
159
Why may peak tension in muscles increase if they are repeatedly activated at a high frequency
The muscle may be reactivated before the previous twitch has fully recovered to result in a tension that rises above that of a single twitch
160
How can tension be increased passively in muscles
Passively stretching a quiescent muscle
161
How does tension vary as stretch increases
As stretch increases, tension increases gradually to a point, beyond which it increases at a faster rate
However if stretched beyond the point where thick and thin filaments don’t overlap, tension will drastically decrease
162
What did AV Hill do
Demonstrated the inverse relationship between velocity of muscle contraction and the force generated
163
What is the formula for the force velocity relationship
(F+a)(v+b) = (Fmax + a)b
Where a and b are constants
164
When is maximum force generated
At isometric tension
165
How much ATP is stored in cells for muscles
Enough for 8 twitches
166
If there is only enough ATP in the cell for 8 twitches, how do we increase the amount of ATP
ATP is regenerated by reacting ADP and phosphocreatine (CP)
167
Give the equation for the reaction of ADP and phosphocreatine
ADP + CP —> ATP + creatine
168
CP provides an immediate backup energy supply. How much ATP can it provide for muscles
Enough for 100 twitches
169
What is the substrate mainly utilised in muscles during intense exercise to produce ATP
Glucose and fatty acid (via the Krebs cycle)
170
How is glucose utilised for ATP in exercise when O2 levels are low
Glucose is anaerobically converged to lactic acid with a limited conversion of ADP to ATP
171
How can proteins contribute to ATP levels for muscles
Proteins can be deaminated to produce ketoacids which can act as intermediates in The Krebs cycle
172
Type 1 muscle fibres have relatively high levels of aerobic enzymes. True or false?
True
173
How do different types of muscle fibres vary in concentrations of aerobic or anaerobic enzymes?
Type 1: high levels of aerobic enzymes
Type 2: intermediate
Type 2b: high levels of anaerobic enzymes
174
Where is smooth muscle found
What is the load on smooth muscle
Lining the walls of hollow organs
The pressure exerted on the walls of the hollow organ by its contents
175
Do smooth muscles always have tonic activation
No
Some muscle like in blood vessels require tonic contraction to maintain pressure
However in the gut, phasic contraction is required to propel contents through the tube
176
Which is faster at contracting: skeletal or smooth muscle
Skeletal
But smooth is better for sustained contraction
177
Are skeletal muscles the same size as smooth muscle
No smooth is much smaller
178
What is the shape and size of skeletal muscle
Spindle shaped often
Typically 3-4μm in diameter and several hundred μm long
179
Why are smooth muscles smooth
They have no visible striations or sarcomeres in their cytoplasm
180
Are thick and thin filaments arranged longitudinally in the cytoplasm it smooth muscle
Yes but they are not aligned transversely
181
Where do filaments attach in smooth muscle
Dense bodies in the cytoplasm and to attachment plaques at the membrane
182
Where can α actin be found
Attachment plaques
183
Describe the T tubular system in smooth muscle
There is none
184
Where is the SR in smooth muscles
There is a vesicular sarcoplasmic reticulum near the membrane
185
What do gap junctions do in smooth muscle
Allow propagation of waves of electrical excitation between cells or transmission of intracellular messengers through the tissue
186
Can smooth muscles generate active tension without nerve stimulation
Yes
187
What is often the role of neural input for smooth muscle
Modulatory
188
Do nerves act specifically on smooth muscule
No the NT released acts over a wide area of smooth muscle
189
All smooth muscle is innervated by sympathetic fibres alone. True or false?
False
There is often dual innervation by sympathetic and parasympathetic fibres with reciprocal functions
190
Is there troponin in smooth muscle
No
191
What does Caldesmon do
Bonds to actin-tropomyosin thin filaments and inhibits cross bridge cycling
192
How does Ca2+ affect caldesmon
Ca2+ causes caldesmon to dissociate from actin, promoting contraction, by binding to the regulatory calcium binding protein calmodulin
193
What is the Ca. CaM and what does it do
The Calcium calmodulin complex
Binds to caldesmon causing it to dissociate from the thin filaments
194
How else can the dissociation of caldesmon from actin be caused (other than by Ca. CaM)
Direct phosphorylation of PKC (protein kinase C)
195
What regulates PKC
Diacylglycerol (DAG)
196
What is DAG a product of
Phospholipase C activation
197
How does Ca2+ directly affect myosin
Calcium binds directly to the cross bridge to increase cross bridge cycling
198
What does the myosin light chain kinase do
How long does this effect last
Phosphorylates the myosin light chain to increase cross bridge cycling
This lasts until dephosphorylation by myosin phosphatase
199
What activates myosin light chain kinase
The calcium calmodulin complex
200
What kind of regulation is myosin light chain kinase phosphorylation
Why?
Covalent regulation
Phosphorylation forms a covalent bond
201
What happens if the myosin light chain is dephosphorylated when attached to the thin filament
What is this called
It remains bound with high affinity
A cross bridge in this state is called a latch bridge
202
What do latch bridges allow
The maintenance of tension without cross bridge cycling and ATP consumption
203
Which is more efficient: smooth muscle or skeletal muscle?
Why is this?
Smooth muscle is 300x more efficient than skeletal in maintained contractions due to latch bridge formation
204
What accounts for the slowness it smooth muscle contraction
The control of cross bridge cycling by biochemical cascades
205
What indicates that the sliding filament mechanism is present in smooth muscle
Smooth muscle shoes a similar force-length relationship to skeletal muscle for isometric contractions
206
Is contraction velocity with maximal stimulation higher in skeletal or smooth muscle
Lower velocity in smooth muscle
207
How can velocity of shortening be increased in smooth muscle
Increased levels of cross bridge phosphorylation
208
Is lots of phosphorylation required for maximum isometric force generation in smooth muscle
No
209
What happens to calcium and the rate of cross bridge phosphorylation in a sustained contraction
Calcium and the rate of cross bridge phosphorylation increase to a peak initially to produce rapid shortening and the subsidise to lower levels while tension is maintained
210
Name 3 organs which have smooth muscle that contacts phasically in response to stretch
Bladder
Uterus
Gut
211
What causes smooth muscle phasic contraction in response to stress in organs like the bladder
Mechanically induced depolarisation due to stretch activated ion channels in the muscle membrane
212
What does tonic stretch induced contraction allow
Compensative adjustment of tension to keep length constant
213
In cardiac and skeletal muscle how is calcium mediated
Through its binding to the TnC subunit of troponin
214
How many calcium binding sites are on a skeletal TnC subunit
Which binding sites are special
4
2 of the sites have a much higher affinity for Ca2+ than Mg2+ and are critical sites for regulation of cross bridge activation
215
Is the T tubule extracellular space
What does this mean
Yes
The total surface area is 6-10x larger than that of a sarcolemmal cylinder alone
216
Where are the T tubule networks found
Between the A and I band in mammalian skeletal muscle
In the Z band in amphibian skeletal muscle and mammalian cardiac muscle
217
What is the terminal cisternae
Where the sarcoplasmic reticulum comes into a close relationship with the T tubules
218
How are the SR and terminal cisternae arranged
The membranes or 2 membrane systems come into close proximity where 2 terminal cisternae sandwich a T tubule
This gives rise to a triad arrangement
219
How much of the tubular surface is triadic regions
70% (in frog muscle)
220
What happens when the tubular membrane in muscle is depolarised
It triggers release of intracellular calcium from the SR, elevating free cytosolic calcium concentration
This activates contractile proteins and initiates mechanical activity
221
What is the stimulation frequency required for tetanus is
a) slow muscle
b) fast muscle
a) 40 per second
| b) 300 per second
222
Which ion channel is particularly common in muscles cell membranes
Are they equally popular on the tubular surface
Sodium
No they are less common there
223
How many types of potassium channels are there in nerve and muscle
1 type predominates in nerve
There are at least 3 types of K channel in muscle
224
Are inward rectifying K channels found in muscle
Yes
225
What are the 3 types of K channel in muscle
One is activated by depolarisation over a time course similar to that in nerve membranes
One is activated over a considerably longer time course of hundreds of ms
The final type is an inward rectifying K channel
226
What is the purpose of the muscle’s inward rectifying K channel
Minimise leak currents to reduce the amount of inward current required to sustain the plateau phase of cardiac APs
227
How does the resting skeletal muscle cell differ from a nerve cell in terms of conductance
Resting skeletal muscle shows a significant chloride conductance
228
What is the point of the Cl- conductance I’m resting skeletal muscle
Important in stabilising membrane potential between episodes of electrical activity
229
What is myotonia congenita
A deficiency of functioning Cl- channels in skeletal muscle which leads to unwanted repetitive AP firing
230
What are responsible for the inward currents that give rise to the regenerative activity in invertebrate muscle
Ca2+ channels
231
What phase of the cardiac AP is Ca2+ responsible for
The plateau phase
232
What may abnormalities associated with calcium permeability lead to?
Pathological changes in dystrophic muscle
233
What is important about fact that the T tubule lamina constitute a restricted extracellular space
Ions can accumulate or be depleted from here as diffusion with the rest of the ECF is v slow
234
What is excitation contraction coupling
The series of events that connect membrane depolarisation with myofilament activation
235
The T tubules are capable of only passive electrical conduction. True or false?
False
They themselves can also propagate action potentials
236
Are t tubules important in excitation - contraction coupling?
Yes they play a vital role in initiating and synchronising contractile activity through the entire cross section of muscle fibre
237
What does excitation contraction coupling begin with
The detection of the T tubular membrane depolarising by a voltage sensor
238
What is a voltage sensor
A modified calcium channel protein located in the tubular membrane of muscle
Its configuration varies steeply with membrane potential
239
What causes the voltage sensor to change conformation
What does this change lead to
Charge movements
Release of Ca2+ into the cytosol from the SR
240
In skeletal muscle, what does elevated cytosolic calcium reflect?
It almost entirely reflects the release from the SR (there is v little influx from the ECF)
241
In skeletal muscles where does the transduction of Ca2+ from the SR to cytoplasm occur
Why do we think this
At the triad
EM studies show foot processes joining the cisternae and tubular membranes in the triad complex.
242
What are the foot processes in the triad thought to be
Cytoplasmic components of the ryanodine receptor
243
Where are the intracellular portions of the ryanodine receptor found
What does this portion receptor act as?
Within the SR membrane
A calcium channel,
the cytoplasmic portion makes up most of the foot process
244
What are the foot processes on the SR close to
Structures embedded in the T tubule membrane, thought to be voltage sensors
245
How are changes in polarisation in the T tubule connected to the SR
Direct mechanical coupling between the ryanodine receptors and voltage sensors
246
What is the result of the coupling of the ryanodine receptors and the voltage sensors on the T tubule
The release of intracellular Calcium ultimately initiates mechanical activity through their binding to troponin
247
What is malignant hyperthermia
A genetic defect of the ryanodine receptor resulting in muscle spasms and excessive heat generation
248
What are the clinical manifestations of malignant hyperthermia usually triggered by
Halothane (a common general anaesthetic)
249
How is Ca re-sequestered after activation
Active transport of Ca2+ into the SR by a membrane Ca-ATPase
250
Where is the Ca-ATPase found
In the longitudinal regions of the SR membrane, remote from the terminal cisternae
251
Describe the Ca-ATPase molecule
Molecular weight of 100kD
Transports 2 Ca2+ for each molecule of ATP hydrolysed
Pumps calcium from the cytosol to SR, building up a thousand fold concentration gradient across the membrane
252
Is the Ca2+ just floating around in the SR
NO
a number of intra-luminal proteins sequester the luminal Ca2+
Eg calsequestrin
253
Name a luminal protein that sequesters luminal Ca2+
Describe it
Calsequestrin
Has a 1:45 binding ratio for Calcium
Occurs most abundantly in the terminal cisternae lumina
254
Why is sequestering required in the SR
To return cytosolic calcium concentration to levels below those required for significant troponin binding thereby ending the twitch
255
How big are cardiac muscle cells compared to skeletal muscle cells
Cardiac muscle cells are significantly shorter (~10 microns in diameter and 200 microns in length)
256
How are cardiac muscle cells linked
They are linked in a branched and end to end fashion by intercalated disks, producing a syncytium
257
Does the syncytium in cardiac muscle cells conduct electrical or mechanism a forces between component cells?
Both
258
At the ultrastructural level, cardiac muscle resembles which other muscle type
How are they similar and different
Skeletal
Both have a SR and T tubule system
Cardiac SR is less developed
The SR - T tubule complex is a dyad in cardiac but a triad in skeletal
259
What are the different functions of different types of cardiac muscle
Contractility
Or
Impulse conduction/
Impulse generation
260
Where are the cardiac muscle cells specialised for impulse conduction/ generation found?
SAN
AVN
Bundle of His
261
Give an overview of a cardiac action potential
There is an initial rapid depolarisation but then after the early overshoot, the ventricular membrane potential falls quickly to 0mV and remains here in a plateau
262
What are the 5 phases of ventricular action potential
Phase 0= very rapid depolarisation
Phase 1= initial Brief rapid repolarisation
2= the plateau
3= terminal repolarisation to Restore membrane potential to its resting potential
4= electrical diastole
263
What causes the initial rapid rising phase of an AP in cardiac muscle
The opening of Na channels
264
In cardiac muscle, what initiates excitation contraction coupling
What follows this
Prolonged inward Ca2+ currents
This produces a long lasting plateau phase
265
Where is the plateau phase in cardiac muscle particularly prominent
In the Purkinje and ventricular fibres
266
How long can a plateau phase be
Up to 500ms after the early upstroke
267
Does verapamil do
Name a similar drug
Blocks calcium channels, diminishing the amplitude of the plateau phase
Nifedipine
268
Discuss membrane resistance during the plateau phase
Membrane resistance is increased in the plateau phase as a result of inward rectification brought about by K channels at such voltages
269
What do inward rectifiers do during the plateau phase
Reduces inward current what would otherwise be required to hold the membrane potential at plateau level
This ultimately minimises the dissipation of calcium concentration gradients across the cell membrane
270
What does the repolarisation of cardiac APs result from
The gradual activation of further potassium channels
The outward current drives the membrane towards the resting level
271
How do APs adjust to heart rate
Why is this
The AP duration appears to adjust inversely to heart rate
To allow appropriate adjustment of the relative durations of systole and diastole in relation to changes in the interval between successive APs
272
What is the primary pacemaker
Why
SAN
These are the cells whose resting potential drifts towards the threshold at a faster rate
273
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How often does the
a) SAN
b) AVN
c) Purkinje fibres
discharge
```
a) 60-80 times/min
b) 40-60
c) 30-40
274
When do the AVN or Purkinje fibres take over control of heart rate
These are secondary pacemakers so take over when there is severe SAN inhibition
275
Which contractile cardiac muscle cells produce pacemaker activity
cardiac muscle cells whose main function in contractile don’t usually produce pacemaker activity
276
What is the normal human heart beat frequency
How do the SAN cells maintain this
70 beats per minute
The membrane of SAN cells have a high background leak conductance that results in intrinsic firing
277
What does the SAN’s pacemaker role dictate
The rate and sequence of activation of different regions of the heart
278
When may the SAN function be abnormal
Sick sinus syndrome
279
What may cause congenital sick sinus syndrome
A mutation of the gene responsible for the formation of the α subunit of SCN5A (a sodium channel)
280
What does the AV ring do
Electrically isolates the ventricles from the atria - the AVN provides the only communication between them
281
What is the role of the AVN when the SAN works just fine
How does it perform this role
To synchronise the sequential atrial and ventricular contractions
Conduction through this node is slower (0.2 m/s) than through the remaining myocardium
282
Do cells in cardiac conducting tissues like the Bundle of His have myofilaments?
Yes but they have fewer, instead they show faster impulse generation and propagation than surrounding myocytes
283
What is the difference in conduction speed between His cells and normal cardiac myocytes
His: 2-5 m/s
Myocytes: 1m/s
284
What are the left and right bundle branches
Which is smaller
Two fans formed by the bundle of His immediately distal to the AVN
The right is smaller and the left divides into anterior/ superior and posterior/ inferior fascicles
285
What is the importance of the fascicles from the left bundle branch in the heart
Impulses from the AVN are conducted through the fascicles to the apex of the ventricles. Impulses are then propagated through surrounding myocardium at a slower rate.
286
What does the pattern of electrical conduction from the bundle branch fascicles result in
A ventricular contraction that optimises extrusion of blood as contraction begins at the apex and spreads to the base of the ventricles
287
When is cardiac muscle in the absolute refractory period
Why is this
I’m between the early rapid depolarisation to the point where the membrane potential is repolarised to ~-40mV
Inactivation of fast Na+ channels
288
When is the cardiac muscle in relative refractory period
From ~-40 to ~-80mV (complete repolarisation)
289
What happens to action potentials in cardiac muscle during the relative refractory period
Evoked APs have smaller amplitudes and rate of rise is conducted more slowly
290
How long is the relative refractory period
It is proportional to the duration of the action potential
291
order the following based on length of refractory period, from smallest to largest:
Ventricular, atrial, Purkinje fibre
Atrial< ventricular < Purkinje
292
Refractory period is directly proportional to heart rate. True or false?
False
The refractory period is inversely proportional to heart rate
293
a) Why do we have a longer refractory period on the heart
| b) What would happen without this
a)To ensure the heart pumps rhythmically at appropriate intervals
The duration of the refractory period in a normal heart allows the impulse from the SAN to propagate throughout the entire myocardium just once
b) re-entry arrhythmia would occur
294
How can re entry arrhythmia be treated
By lengthening the refractory period by pharmacological means
295
Is tetanus possible in the heart?
Why is this?
No the refractory period is too long
It would be detrimental to heart function, in contrast to the situation in skeletal muscle
296
What is the resting potential of smooth muscle
-50 to -70mV
297
Name organs where you may get smooth muscle showing slow AP firing
Vas deferens
| Uterus
298
Name organs where you may get smooth muscle showing plateau potentials
Stomach
| Ureter
299
Name an organ where you may get smooth muscle showing rhythmic oscillations in membrane potential
Intestine
300
What is the effect or tetrodotoxin on smooth muscle
Tetrodotoxin does not block smooth muscle spiking activity as it is produced by VG Calcium channels
301
What is the important of the higher surface area to volume ratio in smooth muscle compared to skeletal muscle
For smooth muscle, it makes the entry of external calcium more important whereas Ca2+ release from the SR is more important in skeletal
302
What initiates mechanical activity in cardiac muscle
Increased [cytosokic Ca2+] following membrane depolarisation, resulting in calcium binding to troponin
303
How many calcium binding sites in cardiac troponin
3
304
What is the most important source of activator calcium in cardiac muscle
From the SR in response to T tubule depolarisation
305
Why is extracellular calcium still important in the heart
Calcium entry provides the stimulus from calcium release from the SR
Thus doubling extracellular calcium will nearly double maximum cardiac contractile force
306
Give 3 differences between the mechanical activation of skeletal and cardiac muscle
1) amount of calcium released
2) how they modulate the strength of contraction
3) the effect of calcium influx
307
How does the amount of calcium released on activation differ between skeletal and cardiac muscle
In skeletal the release of intracellularly stored calcium is well in excess of that required fro maximal contraction
In cardiac, the amount of intracellular calcium released is not supramaximal but is closely influenced by factors which influence inotropy
308
How does skeletal muscle modulate contractile strength
By varying recruitment of activated fibres
309
How does cardiac muscle vary strength of contraction
Intercalated disks link all muscle in a syncytium so all muscles cells must be activated. Therefore the strength of contraction is regulated by the amount of Calcium made available
310
How are cytosolic calcium levels maintained in cardiac muscle between APs
Both surface and SR membranes have calcium ATPase pumps which move Ca2+ into the ECF or SR lumina
Sodium - calcium exchange drives efflux of calcium across the surface membrane
311
How does the Ca - Na pump work in cardiac muscle
It utilises the energy from the influx of Na down the electrochemical gradient, which was established by a Na/K pump
312
How does digitalis and other cardiac glycosides work
Used in management in cardiac failure
They block the Na/K pump so intracellular sodium increases, decreasing its electrochemical gradient, making it harder for the Ca/Na exchanger to remove Ca
Intracellular calcium builds up, increasing contractile force
313
The passive tension-length relationship is much steeper in cardiac muscle than skeletal. True or false?
What does this mean
True
Even resting cardiac muscle is considerably more resistant to stretch than skeletal
314
Active shortening of cardiac muscle takes place on what part of the passive length tension curve
Almost entirely on the part where increased stretch leads to increased contractile force
315
What law may the steep passive length- active tension relationship of cardiac muscle explain
The Frank Starling Law
316
Which 2 ways make the heart a self regulating pump thanks to the Frank Starling Law
Both with respect to demands from the peripheral circulation and in balancing the pumping by the left and right sides of the heart
317
What is the Bowditch effect
When myocardial contractility increases with heart rate
318
What is the Anrep effect briefly
Myocardial contractility increases with afterload
319
Which neurotransmitter slows heart rate
How does it do this
ACh
Increases membrane K conductance which hyperpolarises the membrane of the SAN during diastole
320
Which neurotransmitter reduces cardiac contractility
How
ACh
By resting the low inward calcium current
321
Name 2 sympathetic transmitters of the heart
Noradrenaline
| Adrenaline
322
How do noradrenaline and adrenaline increase heart rate
They increase the rate of pacemaker depolarisation during diastole and in hyperpolarisation early in diastole
Also increase inward calcium current that contributes to the inotropic effect exerted by catecholamines on cardiac function
323
What does the action potential look like after the effect of adrenaline
Shows a higher but shorter plateau
324
What does the ECG waveform record
The changes with time in potentials in the body surface caused by changes in the summated cardiac polarity brought about by electrical events in the myocardium
325
What does a positive deflection on an ECG generally denote
Generally when a depolarising impulse is conducted towards the electrode or if a repolarisation wave is propagated away from the electrode
326
Why are atrial deflections on an ECG smaller
They have smaller muscle mass
327
The P wave is equivalent to an atrial QRS complex. True or false?
True
328
How big should a P wave be
What if it is bigger than this
<0.12s wide and <0.3mV high
Suggests atrial enlargement
329
What should the PQ interval look like
What if it is not
Should be consistent and between 0.12 and 0.24s
If too short: accessory pathways present
If too long: diagnostic of first degree heart block
330
What should the QRS complex look like
What if it doesn’t
<0.12s
If too long: intraventricular conduction defect, including left and right bundle branch block
The sum of deepest QS and tallest R <3.5mV
If greater than this: left ventricular hypertrophy
331
What is the cardiac cycle length
RR or PP
332
How long should the QT interval be
But
Less than 0.45s
But it is frequency dependent
If too long: Long QT Syndrome (may be secondary to drug treatment)
333
The ST segment is usually isoelectric with normal QRS complex. True or false
True
334
What are the 3 major diagnostic categories for which the ECG is useful
Conduction disorders
Rhythm disorders
Disorders of Myocardial metabolism
335
Discuss disorders or rhythm
Arrhythmias May originate in the atria (better tolerated) or in the ventricles
Result in disrupted PQRST sequence
336
When does the muscle relax
When calcium influx stops
337
Other than VG calcium channels, what are other sources of intracellular calcium elevation ?
Receptor-operated calcium permeable channels mediate calcium influx (these are activated by hormones or NTs)
PLC catalysed formation of IP3 from PIP2. IP3 opens calcium channels in the SR
