L1: Cardiac muscle 1 Flashcards
general features of the cardiac muscle
- Involuntary
- Myogenic (contraction initiated by specialised myocytes).
- Cardiomyocytes are electrically coupled.
- Cardiomyocytes are mainly oxidative in metabolism.
- AP triggers excitation-contraction coupling (CICR).
- Heart beats with a constant rhythm that can be modified
by neural or hormonal input. - Cardiomyocytes have fast contraction, & are non-
fatiguable
main cell types in the heart and proportion
Main cell types:
– Cardiac fibroblasts
* majority of cells in the heart
* secrete & maintain connective tissue fibres
– Cardiomyocytes (~30% of all cells)
* Provide majority of myocardial mass
* Carry out myocardial work (contraction)
* Some are very specialized cells (purkinje & nodal)
– Endothelial cells (vascular and endocardial)
– Vascular smooth muscle cells
– Neurons
The muscular tissue of the heart
what cell type provide the majority of myocardial mass yet only make up 30% of all cells in the heart?
cardiomyocytes
intercalated discs at intercellular junctions consist of…
-nexus or gap junctions
-fascia adherens or
intermediate junctions
-macula adherens or
desmosomes (“spot
welds”)
ECM composition:
Extracellular matrix (ECM)
Comprised of:
~60% vascular (each myocyte in close
proximity to capillaries)
~23% substance resembling glycocalyx
7% connective tissue cells
6% empty space
4% collagen
LTCC in skeletal muscle vs cardiac muscle
Similar to skeletal muscle in cardiac muscle: have RyR on junctional SR
Unlike skeletal muscle which has a voltage- dependant interaction between the LTCC( L-type Ca2+ channel) and the RyR (ryanodine receptor) to release Ca2+
-In cardiac myocytes the LTCC is a patent channel-V-gated and the channel itself opens and allows influx of Ca2+
During the AP when depolarisation occurs LTCC opens up-> Ca2+ influx causes big rise in the concentration of Ca2+ in this specialised area( gap between t-tubule and RyR) that triggers the opening of RyR, which are the Ca2+ release channels of the junctional SR.
T-tubule organization in cardiac muscle
Most of the T-tubules are occurring as transverse tubules
T-tubules link along the longitudinal axis of the cell
So when the AP is propagated along the surface sarcolemma and down these t-tubules within the cell it is continuing this propagation in the longitudinal direction. This means that cardiac muscle potential is synchronised throughout the cell to trigger excitation-contraction coupling within a few ms.
mitochondria make up ~ __ % of cardiomyocyte cell volume
40%
Excitation- contraction coupling & Ca2+ induced Ca2+ release
Ca2+ induced Ca2+ release:
Depolarisation of the surface sarcolemma causes the V-gated Ca2+ channels to open( LTCC), a little bit of trigger Ca2+ comes into the cytosol in the region close to where the RyR are on the junctional SR. RyR open-> Ca2+ released into the cytosol.
Ca2+ conc. Is increased very rapidly throughout the whole cytosol of the cell by about 10 x the resting Ca2+ lvl.
Ca2+ is then free to diffuse to the contractile proteins in the myofilaments. Ca2+ binds to troponin-C, triggering cross-bridge cycling.
Contractile proteins are very close to the junctional region of the SR, so the diffusion distance for Ca2+ to trigger cross-bridge cycling is very short within the myocyte!
*Ca2+ ions that come from the outside the cell or from the SR into the cytosol are NOT destroyed they are recycled.
During relaxation- we have removal of cytosolic Ca2+ mostly by reuptake into the SR by SERCA and some of it will be transported out across the sarcolemma by 3Na+/Ca2+ exchanger(! an important component of Ca2+ balance/homeostasis because Ca2+ that comes into the cell during LTCC current/inflow must be removed back from the cell via 3Na+/Ca2+ exchanger). Also have the 3Na+/ 2K+ pump.( maintain Na+ gradient). And V-gated Na+ and K+ channels that trigger the AP. ( part of AP)
With each electrical stimulation get a rapid increase in intracellular Ca2+, which then decreases again equally rapidly as Ca2+ is taken back up into SR and pumped outside the sarcolemma via 3Na+/Ca2+ exchange.
During steady state with each heartbeat in every muscle cell we have this highly regular amount of Ca2+ released and cycled per beat.
Importance of t-tubules
For excitation-contraction coupling to be efficient we have to have the LTCC in the t-tubules close to the RyR. In a diseased cell whereby the junctional SR is slightly distorted or t-tubules have been lost in some parts of the cell altogether the excitation-contraction coupling is not going to be as well synchronised, so instead of a very rapid upstroke with a Ca2+ transient, will have a much slower upstroke, with a much slower/ delayed twitch/contraction occurring-> weaker heartbeat altogether.
Cav-3 is a marker of the surface sarcolemma in the t-tubule membranes.
RyR2 in blue.
In a healthy cell- very regular striations.
Pulmonary artery hypertension: Heart failure: hypertrophy of the right ventricle: can see that the t-tubular system is distorted , have lost RyR and in other areas- have higher density of RyR but with no t-tubules.
These hypertrophy cells prior to HF are not performing well, so this animal model developed HF within a few weeks.
Just prior to HF- can see disruption of the t-tubular system seems to occur prior to HF.
Think of a diseased cardiomyocyte where all the t-tubules were disrupted and not close to RyR throughout the whole cell. When LTCC open- have influx of Ca2+ but will dissipate before it reaches RyR. The gain of E-C coupling is reduced, because of the distorted t-tubules -> weaker contraction. If the entire heart is like that-> trouble.
L-type Ca2+ channels(DHPR) are inhibited by…?
-SR Ca2+ release
-inhibited by dihydropyridines ( Ca2+ channel blockers), Mg2+ etc
-inhibited by low plasma [Ca2+] and vice versa. The channels themselves close or are inhibited by low cytosolic Ca2+ conc. During diastole it is important that we don’t have Ca2+ leaking via LTCC.
L-type Ca2+ channels(DHPR) are stimulated by…?
-activated by depolarisation > -40mV
-stimulated by catecolamines
L-type Ca2+ channels(DHPR) are stimulated by…?
-activated by depolarisation > -40mV
-stimulated by catecolamines
what happens if not all Ca2+ is removed during diastole?
In a situation where Ca2+ is not being removed completely during diastole ( happens in diseased hearts) the gradient for Ca2+ to move into the cell through LTCC is reduced-> can cause a much weaker contraction in the cells.
what is calsequestrin and what’s its role?
Calsequestrin is a calcium-binding protein primarily found in the sarcoplasmic reticulum (SR) of muscle cells. It is especially abundant in the SR of cardiac and slow-twitch skeletal muscle fibers.
The primary function of calsequestrin is to act as a calcium buffer and regulator within the SR. It has a high calcium-binding capacity, allowing it to bind and store large amounts of calcium ions (Ca^2+) within the SR lumen. By binding to calcium, calsequestrin helps maintain a high concentration of calcium within the SR, which is crucial for muscle contraction.
what is phospholamban and its action?
Phospholamban acts as an inhibitor of SERCA pump activity when it is not phosphorylated. In its non-phosphorylated form, phospholamban binds to SERCA and reduces its affinity for calcium ions, thereby slowing down the rate of calcium uptake into the SR. This inhibition ensures that the SR does not take up excessive amounts of calcium, allowing for proper relaxation of the muscle.
However, when phospholamban is phosphorylated by protein kinase A (PKA) or calcium-calmodulin-dependent protein kinase (CaMK), its inhibitory effect on SERCA is relieved. Phosphorylated phospholamban undergoes a conformational change, reducing its binding affinity to SERCA and allowing for increased calcium transport into the SR. This phosphorylation-dependent modulation of phospholamban activity promotes faster muscle relaxation and enhances the ability of the SR to store calcium for subsequent contractions.
Phospholamban acts as a regulator of SERCA activity. When phospholambin is phosphorylated such as during beta-adrenergic activation it releases its inhibition on the pump and allows it to pump/reuptake Ca2+ much more quickly.
When we are at rest and our HR is relatively slow, there is not urgency to clear the cytosolic Ca2+ very rapidly. But if we have beta-adrenergic stimulation( e.g exercise) our HR goes up still want to maintain a good Ca2+ gradient to initiate good force of contraction- important that we take up Ca2+ into the SR as quickly as possible- that is when phosphorylation of phospholamban occurs so it releases the inhibition to increase the rate of Ca2+ uptake into SR.
what are the 4 important Ca2+ transport proteins
what happens if Ca2+ efflux is decreased?
If Ca2+ efflux is decreased: Ca2+ will accumulate inside the cell leading to:
1) a higher SR Ca2+ content
2) Subsequently, a bigger Ca2+ transient
3) On the next beat: Increased Ca2+ extrusion to balance influx
More Ca2+ taken up between beats into SR-> increases Ca2+ load in SR-> causes the next beat to have a bigger Ca2+ transient because the gain of E-C coupling has been increased.
The following Ca2+ transient will need to have an increased Ca2+ extrusion across the sarcolemma to balance the influx.
A means of how on a beat-to-beat basis the cells can regulate the strength of contraction- automatic balance between Ca2+ influx and efflux.
*if Ca2+ influx is increased same 1,2,3 will apply
myocyte relaxation
Relaxation is important. Relaxation allows the filling of the chambers. Ventricular filling-> CO.
When cytosolic Ca2+ is reduced-> Ca2+ unbinds from troponin-C
(SERCA takes up the bulk of Ca2+ into SR)
Na+/ Ca2+ exchanger: reverse and forward mode
Na+/Ca2+ exchanger is electrogenic. It has a stoichiometry that allows it to change the charge across the cell membrane.
The exchanger can work in forwards or reverse mode:
Forward mode: during diastole/relaxation, it works to extrude/take out Ca2+ across the SL
In reverse mode such as during the plateu phase of the AP it brings Ca2+ into the cell - contributes to Ca2+ current.
Forward mode of NCX
Ca2+ extrusion
Reverse mode of NCX
Ca2+ entry
Maintains the AP in the depolarised state for a little longer
Ca2+ entry by NCX stimulated by:
low intracellular Ca2+
High intracellular Na+
more +ve membrane potential
Ca2+ extrusion by NCX stimulated by:
high intracellular Ca2+
low intracellular Na+
-ve membrane potential
