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04
Cardiac Excitation-Contraction Coupling
45
Pharmacology
Undergraduate 1
12/01/2016

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Term
Is the architecture of cardiac muscle similar to skeletal muscle?
Definition
Yes. They are both made up of the same repeating units (sarcomeres) which are bordered by the Z-discs, incorporating myofibrils, SR, t-tubules, mitochondria and nuclei.
Term
Describe the A-band
Definition
contains thick filaments which are mainly composed of the protein myosin
Term
Describe the I-band
Definition
contains thin filaments which are mainly composed of the protein actin
Term
How are the thin and thick filaments arranges?
Definition
Thin filaments are attached to te Z-discs and are arranged in a hexagonal array.

Thick filaments are organised by the M-line - also in a hexagonal arrangement.
Term
What is the role of titin?
Definition
Titin is associated with thick filaments, it imparts series elasticity and is anchored by the Z-discs.
Term
Describe the thin filament structure
Definition
- Actin filament has a double stranded rope-like structure.
- Long protein tropomyosin lies in the groove made by 2 actin strands
- Each strand of the actin filament has a repeating structure composed of 7 actin monomers polymerised together and associated with one tropomyosin protein units.
Term
What is the troponin complex?
Definition
situated 38.5nm along the actin-tropomyosin filament there is another protein complex called troponin. The complex is made up of 3 subunits: Troponin-C, Troponin-I and Troponin-T.
Term
Describe Troponin C
Definition
moleculare weight: 18000
role: binds Ca2+ ions to produce a conformational change in Troponin 1
Term
Describe Troponin I
Definition
molecular weight: 25000
role: binds to actin. It's role is to inhibit the binding of myosin to actin
Term
Describe Troponin T
Definition
molecular weight: 42000
role: binds to tropomyosin, interlocking them to form a troponintropmyosin complex
Term
Describe the thick filament structure
Definition
- Each myosin molecule is tethered to the thick filament by its tail with the head sticking out.
- Each thick filament is at the centre of a hexagonal array of thin filaments
- made up of 300 individual myosin molecules packed together
Term
Describe the head of the thick filament
Definition
2 individual subunits
known as crossbridges
site of ATP hydrolysis and consequent tension generation
Term
How do t-tubules enter?
Definition
- they invaginate muscle fibres at the level of the Z-line
- they are continuous with the surface membrane (sarcolemma) of the muscle fibre and contain ECF.
Term
How is the saroplasmic reticulum (SR) related?
Definition
- made up of longitudinal and terminal elements
- terminal cisternae of SR are located very closely to the tubules (crucial for ECC in cardiac muscle)
- acts as a calcium store!!
Term
What is the outside face of the SR decorated with?
Definition
SR Ca2+ release channels (ryanodine receptors - RYRs)
Term
Which channels are located in the wall of the t-tubule?
Definition
L-type Ca2+ channels (DHPR)
they are situated directly over the SR Ca2+ release channels
Term
How does the RYR/DHPR arrangement differ from skeletal to cardiac muscle?
Definition
skeletal: DHPRs are arranged in tetrads over a RYR
cardiac: fewer DHPRs and arrangement is less systematic (almost random with respect to RYRs)
Term
List the similarities between cardiac and skeletal muscle (4)
Definition
1. both are striated
2. interdigitating thin and thick filaments giving characteristic A and I bands
3. Thin filament regulatory proteins such as tropomyosin and troponin are present in both muscle types.
4. identical cross bridge cycle
Term
List and explain the differences between cardiac and skeletal muscle regarding t-tubules
Definition
1. T-tubules wider in cardiac muscle (reduces ionic depletion)
2. T-tubules enter the cells at Z-lines in cardiac muscle and A-I boundary in skeletal muscle
Term
List and explain the differences between cardiac and skeletal muscle regarding Ca2+
Definition
1. Cardiac troponin-C can ony bind 3 Ca2+ ions compared to 4 for skeletal muscle (two of these sites can also bind Mg2+)
2. Mechanism of SR Ca2+ release is different
Term
Any other differences between cardiac and skeletal muscle?
Definition
Fewer DHPRs in cardiac muscle
Term
What is required for RYRs to open in cardiac muscle?
Definition
Ca2+ must enter through L-type Ca2+ channels to cause the RYRs to open. Hence the name 'calcium-induced calcium release'.
Term
Describe the Cardiac Excitation-Contraction Coupling Mechanism
Definition
1) AP travels across the surface membrane of the ventricular cell and down the t-tubules.
2) This will depolarise the t-tubular membrane where the L-type Ca2+ channels (DHPRs) are concentrated
3) Ca2+ channels in SR membrane situated directly opposite t-tubules are Ca2+ release channels (the RYRs). The RYRs and SHPRs are coupled together and physically link the t tubules and SR membranes
4) Ca2+ entry through L-type channels cause SR Ca2+ release channels to open and Ca2+ floods out of the SR into the cytoplasm.
Term
What induces membrane depolarisation?
Definition
opening of Na+ channels which underlies the upstroke of the AP
Term
What does this tell us about where the Ca2+ required for contraction comes from?
Definition
A small amount of Ca2_ crossing the cell membrane via Ca2+ channels causes a larger amount of Ca2+ to be released from the SR.

20% of the Ca2+ for each contraction comes from outside the cells with the remaining 80% released from the SR.
Term
How does relaxation occur?
Definition
Ca2+ must be removed from the cytoplasm by one of three pathways
Term
List the 3 pathways in which Ca2+ is removed so relaxation can occur
Definition
1. Ca2+ pumped back into the SR by ATP-dependent Ca2+ pumps.
2. Ca2+ is removed from the cell via Na/Ca exchanger
3. Ca2+ is removed from the cell via sarcolemma Ca2+ ATPase
Term
What is the fate of Ca2+ removed for relaxation?
Definition
80% returned to the SR.
20% leaves the cell: 18-19% via the NCX and 1-2% via the sarcolemmal ca2+ ATPase.
Term
Describe the events that follow activation of heart muscle cells via the AP
Definition
- rise of Ca2+ in the cytoplasm
- Ca2+ binds to troponin-C which acts as a molecular switch to allow cross bridge cycling to occur.
Term
How is a steady state level of Ca2+ in cells maintained? and why?
Definition
The NCX uses the power of the inwardly directed electro-chemical gradient for Na+ to extrude Ca2+ from the cell against its concentration gradient (not an active process).

The amount of Ca2+ that entered during excitation has to be removed from th cell before the next beat.
Term
How many Na+ ions does it take to remove of Ca2+ ion?
Definition
3
Term
What does it mean that NCX is electrogenic?
Definition
generates electricity in living tissues/organisms
Term
Why isn't the sarcolemmal Ca2+ ATPase efficient enough?
Definition
It is a high affinity pump but has a slow turnover rate in comparison. Relaxation of a single beat using this mech would take almost 60s.
Term
How does binding of Ca2+ to troponin C initiate contraction?
Definition
When Ca2+ binds to Tn-C, this initiates a series of changes in protein-protein interactions and eventually allow cross-bridge cycling to occur
Term
Describe the troponin complex in a relaxed state (absence of calcium)
Definition
- tropomyosin is bound to actin filament
- Tn-T is bound to tropomyosin and Tn-I
- Tn-I strongly bound to actin
- Tn-C is bound weakly to Tn-I
Term
What is the significance of Tn-I being strongly bound to actin?
Definition
this blocks the actin-myosin binding site
therefore myosin cannot bind to actin
Term
How does the troponin complex change in the active state?
Definition
1) calcium levels rise in the cytoplasm and binds to Tn-C
2) Tn-C binds more strongly to Tn-I
3) Tn-I can no longer bind to actin
Term
What follows Tn-I being no longer able to bind to actin?
Definition
a change in the binding of Tn-I to Tn-T and subsequent changes in the binding of Tn-T to tropomyosin and tropomyosin to actin.
Term
What causes the actin binding site to be uncovered?
Definition
- tropomyosin molecules moving further into the groove of the actin filament
- myosin site on actin is uncovered and the myosin cross bridge can now bind actin
Term
What happens if calcium is lowered again?
Definition
Ca2+ dissociate from Tn-C, Tn-I will bind once again to actin and the myosin binding site will be blocked.
Term
Describe the myosin head in a resting sarcomere
Definition
- each head is energised and charged with the energy that will be used to power a contraction.
- each head points away from the M line (cocked)
Term
What causes a myosin head to cock
Definition
energy!!
obtained by breaking down ATP
the myosin head functions as ATPase
at the start of contraction, the breakdown products (ADP and phosphate) remain bound to the myosin head.
Term
What happens once the active sites on actin are exposed?
Definition
the energised myosin heads bind to them forming cross-bridges and energy stored in resting state is released as myosin heads pivot towards the M line.
POWER STROKE
ADP and P released.
Term
How does the cross bridge become detached?
Definition
another ATP binds to the myosin head, the link between the myosin head and the active site on actin is broken.

active site is now exposed.
Term
How is the actin reactivated?
Definition
when the free myosin head splits ATP into ADP and P. The energy released is used to cock the head.
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