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86-523: T-tubules ( transverse tubules ) are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells . With membranes that contain large concentrations of ion channels , transporters, and pumps, T-tubules permit rapid transmission of the action potential into the cell, and also play an important role in regulating cellular calcium concentration. Through these mechanisms, T-tubules allow heart muscle cells to contract more forcefully by synchronising calcium release from

172-647: A gene . Figure 3 shows the important ion channels involved in the cardiac action potential, the current (ions) that flows through the channels, their main protein subunits (building blocks of the channel), some of their controlling genes that code for their structure, and the phases that are active during the cardiac action potential. Some of the most important ion channels involved in the cardiac action potential are described briefly below. Hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels) are located mainly in pacemaker cells, these channels become active at very negative membrane potentials and allow for

258-446: A brief flow of potassium ions out of the cell, making the membrane potential slightly more negative. This is referred to as a 'notch' on the action potential waveform. There is no obvious phase 1 present in pacemaker cells. This phase is also known as the "plateau" phase due to the membrane potential remaining almost constant, as the membrane slowly begins to repolarize. This is due to the near balance of charge moving into and out of

344-458: A neighbouring cell, through gap junctions . When this happens, the voltage within the cell increases slightly. If this increased voltage reaches the threshold potential (approximately −70 mV) it causes the Na channels to open. This produces a larger influx of sodium into the cell, rapidly increasing the voltage further to around +50 mV, i.e. towards the Na equilibrium potential. However, if

430-421: A net displacement of charges across the membrane, which are unable to immediately re-enter the cell to restore the electrical equilibrium. Therefore, their slow re-entrance in the cell needs to be counterbalanced or the cell would slowly lose its membrane potential. The second purpose, intricately linked to the first, is to keep the intracellular concentration more or less constant, and in this case to re-establish

516-456: A protein, called a G s -protein (s for stimulatory). Activation of this G-protein leads to increased levels of cAMP in the cell (via the cAMP pathway ). cAMP binds to the HCN channels (see above), increasing the funny current and therefore increasing the rate of depolarization, during the pacemaker potential. The increased cAMP also increases the opening time of L -type calcium channels, increasing

602-496: A receptor located on the outside of the pacemaker cell, called an M2 muscarinic receptor . This activates a G i -protein (I for inhibitory), which is made up of 3 subunits (α, β and γ) which, when activated, separate from the receptor. The β and γ subunits activate a special set of potassium channels, increasing potassium flow out of the cell and decreasing membrane potential, meaning that the pacemaker cells take longer to reach their threshold value. The G i -protein also inhibits

688-436: A scaffold to which the muscle fibre can adhere. Through transmembrane proteins in the plasma membrane, the actin skeleton inside the cell is connected to the basement membrane and the cell's exterior. At each end of the muscle fibre, the surface layer of the sarcolemma fuses with a tendon fibre, and the tendon fibres, in turn, collect into bundles to form the muscle tendons that adhere to bones. The sarcolemma generally maintains

774-438: A set value (around -40 mV; known as the threshold potential) or until it is depolarized by another action potential, coming from a neighboring cell. The pacemaker potential is thought to be due to a group of channels, referred to as HCN channels (Hyperpolarization-activated cyclic nucleotide-gated) . These channels open at very negative voltages (i.e. immediately after phase 3 of the previous action potential; see below) and allow

860-431: A signalling chemical travelling the distance between the sarcolemma and the sarcoplasmic reticulum. It was therefore suggested that pouches of membrane reaching into the cell might explain the very rapid onset of contraction that had been observed. It took until 1897 before the first T-tubules were seen, using light microscopy to study cardiac muscle injected with India ink .  Imaging technology advanced, and with

946-405: A transient cell swelling. Returning the extracellular solution to a normal osmolarity allows the cells to return to their previous size, again leading to detubulation. The idea of a cellular structure that later became known as a T-tubule was first proposed in 1881. The very brief time lag between stimulating a striated muscle cell and its subsequent contraction was too short to have been caused by

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1032-510: Is affected, but not controlled by the autonomic nervous system . The sympathetic nervous system (nerves dominant during the body's fight-or-flight response ) increase heart rate (positive chronotropy ), by decreasing the time to produce an action potential in the SAN. Nerves from the spinal cord release a molecule called noradrenaline , which binds to and activates receptors on the pacemaker cell membrane called β1 adrenoceptors . This activates

1118-474: Is located at the junction of the A and I bands. Cardiac action potential Rate dependence of the action potential is a fundamental property of cardiac cells and alterations can lead to severe cardiac diseases including cardiac arrhythmia and sometimes sudden death. Action potential activity within the heart can be recorded to produce an electrocardiogram (ECG). This is a series of upward and downward spikes (labelled P, Q, R, S and T) that represent

1204-429: Is more negative than the outside. The main ions found outside the cell at rest are sodium (Na ), and chloride (Cl ), whereas inside the cell it is mainly potassium (K ). The action potential begins with the voltage becoming more positive; this is known as depolarization and is mainly due to the opening of sodium channels that allow Na to flow into the cell. After a delay (known as the absolute refractory period ),

1290-496: Is potentially responsible for the increasing number of T-tubules seen as muscles grow. T-tubules are an important link in the chain from electrical excitation of a cell to its subsequent contraction (excitation-contraction coupling). When contraction of a muscle is needed, stimulation from a nerve or an adjacent muscle cell causes a characteristic flow of charged particles across the cell membrane known as an action potential . At rest, there are fewer positively charged particles on

1376-515: Is the classic athletic heart syndrome . Sustained training of athletes causes a cardiac adaptation where the resting SAN rate is lower (sometimes around 40 beats per minute). This can lead to atrioventricular block , where the signal from the SAN is impaired in its path to the ventricles. This leads to uncoordinated contractions between the atria and ventricles, without the correct delay in between and in severe cases can result in sudden death. The speed of action potential production in pacemaker cells

1462-424: Is vital for the plateau phase of the action potential (see phase 2, below) and is a fundamental step in cardiac excitation-contraction coupling . There are important physiological differences between the pacemaker cells of the sinoatrial node , that spontaneously generate the cardiac action potential and those non-pacemaker cells that simply conduct it, such as ventricular myocytes ). The specific differences in

1548-515: The T-tubule membrane of ventricular cells, whereas the T-type channels are found mainly within atrial and pacemaker cells , but still to a lesser degree than L-type channels. These channels respond to voltage changes across the membrane differently: L-type channels are activated by more positive membrane potentials, take longer to open and remain open longer than T-type channels. This means that

1634-456: The atria to contract, to the atrioventricular node (AVN) , which slows down conduction of the action potential from the atria to the ventricles . This delay allows the ventricles to fully fill with blood before contraction. The signal then passes down through a bundle of fibres called the bundle of His , located between the ventricles, and then to the Purkinje fibers at the bottom (apex) of

1720-428: The connexin family of proteins, that form a pore through which ions (including Na , Ca and K ) can pass. As potassium is highest within the cell, it is mainly potassium that passes through. This increased potassium in the neighbour cell causes the membrane potential to increase slightly, activating the sodium channels and initiating an action potential in this cell. (A brief chemical gradient driven efflux of Na+ through

1806-531: The connexon at peak depolarization causes the conduction of cell to cell depolarization, not potassium.) These connections allow for the rapid conduction of the action potential throughout the heart and are responsible for allowing all of the cells in the atria to contract together as well as all of the cells in the ventricles. Uncoordinated contraction of heart muscles is the basis for arrhythmia and heart failure. Ion channels are proteins that change shape in response to different stimuli to either allow or prevent

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1892-429: The sarcoplasm of the muscle cell, forming membranous tubules radially and longitudinally within the fiber called T-tubules or transverse tubules. On either side of the transverse tubules are terminal cisternal enlargements of the sarcoplasmic reticulum (termed endoplasmic reticulum in nonmuscle cells). A transverse tubule surrounded by two SR cisternae are known as a triad, and the contact between these structures

1978-492: The sarcoplasmic reticulum throughout the cell. T-tubule structure and function are affected beat-by-beat by cardiomyocyte contraction, as well as by diseases, potentially contributing to heart failure and arrhythmias . Although these structures were first seen in 1897, research into T-tubule biology is ongoing. T-tubules are tubules formed from the same phospholipid bilayer as the surface membrane or sarcolemma of skeletal or cardiac muscle cells. They connect directly with

2064-460: The sodium (Na ) and potassium (K ) ions are maintained by the sodium-potassium pump which uses energy (in the form of adenosine triphosphate (ATP) ) to move three Na out of the cell and two K into the cell. Another example is the sodium-calcium exchanger which removes one Ca from the cell for three Na into the cell. During this phase the membrane is most permeable to K , which can travel into or out of cell through leak channels, including

2150-578: The sodium-calcium exchanger resulting in the increase in membrane potential (as a +3 charge is being brought into the cell (by the 3Na ) but only a +2 charge is leaving the cell (by the Ca ) therefore there is a net charge of +1 entering the cell). This calcium is then pumped back into the cell and back into the SR via calcium pumps (including the SERCA ). This phase consists of a rapid, positive change in voltage across

2236-437: The Ca current through the channel, speeding up phase 0. The parasympathetic nervous system ( nerves dominant while the body is resting and digesting) decreases heart rate (negative chronotropy ), by increasing the time taken to produce an action potential in the SAN. A nerve called the vagus nerve , that begins in the brain and travels to the sinoatrial node, releases a molecule called acetylcholine (ACh) which binds to

2322-439: The SR. These calcium ions are responsible for the contraction of the heart. Calcium also activates chloride channels called I to2 , which allow Cl to enter the cell. Increased calcium concentration in the cell also increases activity of the sodium-calcium exchangers, while increased sodium concentration (from the depolarisation of phase 0) increases activity of the sodium-potassium pumps. The movement of all these ions results in

2408-468: The T-tubule and sarcoplasmic reticulum, known as local control). Proteins such as the sodium-calcium exchanger and the sarcolemmal ATPase are located mainly in the T-tubule membrane. The sodium-calcium exchanger passively removes one calcium ion from the cell in exchange for three sodium ions. As a passive process it can therefore allow calcium to flow into or out of the cell depending on the combination of

2494-484: The T-tubule membrane compared to the rest of the sarcolemma. Furthermore, beta adrenoceptors are also highly concentrated in the T-tubular membrane, and their stimulation increases calcium release from the sarcoplasmic reticulum. As the space within the lumen of the T-tubule is continuous with the space that surrounds the cell (the extracellular space), ion concentrations between the two are very similar. However, due to

2580-449: The T-type channels contribute more to depolarization (phase 0) whereas L-type channels contribute to the plateau (phase 2). In the heart's conduction system electrical activity that originates from the sinoatrial node (SAN) is propagated via the His - Purkinje network, the fastest conduction pathway within the heart. The electrical signal travels from the sinoatrial node, which stimulates

2666-444: The action potential terminates as potassium channels open, allowing K to leave the cell and causing the membrane potential to return to negative, this is known as repolarization . Another important ion is calcium (Ca ) , which can be found inside the cell in the sarcoplasmic reticulum (SR) where calcium is stored, and is also found outside of the cell. Release of Ca from the SR, via a process called calcium-induced calcium release ,

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2752-569: The action potential, the L-type Ca channels close, while the slow delayed rectifier (I Ks ) K channels remain open as more potassium leak channels open. This ensures a net outward positive current, corresponding to negative change in membrane potential , thus allowing more types of K channels to open. These are primarily the rapid delayed rectifier K channels (I Kr ) and the inwardly rectifying K current, I K1 . This net outward, positive current (equal to loss of positive charge from

2838-455: The advent of transmission electron microscopy the structure of T-tubules became more apparent leading to the description of the longitudinal component of the T-tubule network in 1971. In the 1990s and 2000s confocal microscopy enabled three-dimensional reconstruction of the T-tubule network and quantification of T-tubule size and distribution, and the important relationships between T-tubules and calcium release began to be unravelled with

2924-452: The appropriate proteins (in particular L-type calcium channels) are located within the T-tubule membrane. Junctophilin-2 is encoded by the gene JPH2 and helps to form a junction between the T-tubule membrane and the sarcoplasmic reticulum, vital for excitation-contraction coupling . Titin capping protein known as telethonin is encoded by the TCAP gene and helps with T-tubule development and

3010-480: The calcium that enters at the sarcolemma has to diffuse gradually throughout the cell, activating the ryanodine receptors much more slowly as a wave of calcium leading to less forceful contraction. As the T-tubules are the primary location for excitation-contraction coupling, the ion channels and proteins involved in this process are concentrated here - there are 3 times as many L-type calcium channels located within

3096-414: The case of abnormal automaticity the changes are in electrotonic environment , caused, for example, by myocardial infarction . The standard model used to understand the cardiac action potential is that of the ventricular myocyte. Outlined below are the five phases of the ventricular myocyte action potential, with reference also to the SAN action potential. In the ventricular myocyte, phase 4 occurs when

3182-414: The cell is at rest, in a period known as diastole . In the standard non-pacemaker cell the voltage during this phase is more or less constant, at roughly -90 mV. The resting membrane potential results from the flux of ions having flowed into the cell (e.g. sodium and calcium), the flux of ions having flowed out of the cell (e.g. potassium, chloride and bicarbonate), as well as the flux of ions generated by

3268-484: The cell membrane ( depolarization ) lasting less than 2 ms in ventricular cells and 10–20 ms in SAN cells. This occurs due to a net flow of positive charge into the cell. In non-pacemaker cells (i.e. ventricular cells), this is produced predominantly by the activation of Na channels , which increases the membrane conductance (flow) of Na (g Na ). These channels are activated when an action potential arrives from

3354-439: The cell) causes the cell to repolarize. The delayed rectifier K channels close when the membrane potential is restored to about -85 to -90 mV, while I K1 remains conducting throughout phase 4, which helps to set the resting membrane potential Ionic pumps as discussed above, like the sodium-calcium exchanger and the sodium-potassium pump restore ion concentrations back to balanced states pre-action potential. This means that

3440-426: The cell. T-tubules contain a higher concentration of L-type calcium channels than the rest of the sarcolemma and therefore the majority of the calcium that enters the cell occurs via T-tubules. This calcium binds to and activates a receptor, known as a ryanodine receptor , located on the cell's own internal calcium store, the sarcoplasmic reticulum. Activation of the ryanodine receptor causes calcium to be released from

3526-652: The cell. The rapid spread of the action potential along the T-tubule network activates all of the L-type calcium channels near-simultaneously. As T-tubules bring the sarcolemma very close to the sarcoplasmic reticulum at all regions throughout the cell, calcium can then be released from the sarcoplasmic reticulum across the whole cell at the same time. This synchronisation of calcium release allows muscle cells to contract more forcefully. In cells lacking T-tubules such as smooth muscle cells , diseased cardiomyocytes, or muscle cells in which T-tubules have been artificially removed,

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3612-419: The cell. During this phase delayed rectifier potassium channels (I ks ) allow potassium to leave the cell while L-type calcium channels (activated by the influx of sodium during phase 0) allow the movement of calcium ions into the cell. These calcium ions bind to and open more calcium channels (called ryanodine receptors) located on the sarcoplasmic reticulum within the cell, allowing the flow of calcium out of

3698-573: The chances of recovery. Heart failure can also cause the near-complete loss of T-tubules from atrial cardiomyocytes, reducing atrial contractility and potentially contributing to atrial fibrillation . Structural changes in T-tubules can lead to the L-type calcium channels moving away from the ryanodine receptors. This can increase the time taken for calcium levels within the cell to rise leading to weaker contractions and arrhythmias . However, disordered T-tubule structure may not be permanent, as some suggest that T-tubule remodelling might be reversed through

3784-447: The channel. The pore formed by an ion channel is aqueous (water-filled) and allows the ion to rapidly travel across the membrane. Ion channels can be selective for specific ions, so there are Na , K , Ca , and Cl specific channels. They can also be specific for a certain charge of ions (i.e. positive or negative). Each channel is coded by a set of DNA instructions that tell the cell how to make it. These instructions are known as

3870-402: The channels cannot be opened regardless of the strength of the excitatory stimulus—this gives rise to the absolute refractory period. The relative refractory period is due to the leaking of potassium ions, which makes the membrane potential more negative (i.e. it is hyperpolarised), this resets the sodium channels; opening the inactivation gate, but still leaving the channel closed. Because some of

3956-423: The compositions of the compartments to be controlled by selective transport through the membrane. Membrane proteins, such as ion pumps , may create ion gradients with the consumption of ATP , that may later be used to drive transport of other substances through the membrane ( co-transport ) or generate electrical impulses such as action potentials . A special feature of the sarcolemma is that it invaginates into

4042-424: The concentration of calcium outside the cell falls ( hypocalcaemia ), the concentration of calcium within the T-tubule remains relatively constant, allowing cardiac contraction to continue. As well as T-tubules being a site for calcium entry into the cell, they are also a site for calcium removal. This is important as it means that calcium levels within the cell can be tightly controlled in a small area (i.e. between

4128-403: The depolarization (voltage becoming more positive) and repolarization (voltage becoming more negative) of the action potential in the atria and ventricles . Similar to skeletal muscle, the resting membrane potential (voltage when the cell is not electrically excited) of ventricular cells is around −90 millivolts (mV; 1 mV = 0.001 V), i.e. the inside of the membrane

4214-442: The depolarization phase. However, as the membrane potential continues to become more positive, the channel begins to allow the passage of K out of the cell. This outward flow of potassium ions at the more positive membrane potentials means that the K ir can also aid the final stages of repolarisation. The voltage-gated potassium channels (K v ) are activated by depolarization. The currents produced by these channels include

4300-424: The different membrane pumps, being perfectly balanced. The activity of these pumps serve two purposes. The first is to maintain the existence of the resting membrane potential by countering the depolarisation due to the leakage of ions not at the electrochemical equilibrium (e.g. sodium and calcium). These ions not being at the equilibrium is the reason for the existence of an electrical gradient, for they represent

4386-402: The discovery of calcium sparks . While early work focussed on ventricular cardiac muscle and skeletal muscle, in 2009 an extensive T-tubule network in atrial cardiac muscle cells was observed. Ongoing research focusses on the regulation of T-tubule structure and how T-tubules are affected by and contribute to cardiovascular diseases. The structure of T-tubules can be altered by disease, which in

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4472-462: The extracellular solution that surrounds the cells. These agents increase the osmolarity of the extracellular solution, causing the cells to shrink. When these agents are withdrawn, the cells rapidly expand and return to their normal size. This shrinkage and re-expansion of the cell causes T-tubules to detach from the surface membrane. Alternatively, the osmolarity of the extracellular solution can be decreased, using for example hypotonic saline, causing

4558-406: The first few weeks of life. They are found in ventricular muscle cells in most species, and in atrial muscle cells from large mammals. In cardiac muscle cells, across different species, T-tubules are between 20 and 450 nanometers in diameter and are usually located in regions called Z-discs where the actin myofilaments anchor within the cell. T-tubules within the heart are closely associated with

4644-439: The first from the beginning of phase 0 until part way through phase 3; this is known as the absolute refractory period during which it is impossible for the cell to produce another action potential. This is immediately followed, until the end of phase 3, by a relative refractory period, during which a stronger-than-usual stimulus is required to produce another action potential. These two refractory periods are caused by changes in

4730-434: The flow of K into the cell. This influx of potassium, however, is larger when the membrane potential is more negative than the equilibrium potential for K (~-90 mV). As the membrane potential becomes more positive (i.e. during cell stimulation from a neighbouring cell), the flow of potassium into the cell via the K ir decreases. Therefore, K ir is responsible for maintaining the resting membrane potential and initiating

4816-444: The heart may contribute to weakness of the heart muscle or abnormal heart rhythms. The alterations seen in disease range from a complete loss of T-tubules to more subtle changes in their orientation or branching patterns. T-tubules may be lost or disrupted following a myocardial infarction , and are also disrupted in the ventricles of patients with heart failure , contributing to reduced force of contraction and potentially decreasing

4902-494: The heart, causing ventricular contraction. In addition to the SAN, the AVN and Purkinje fibres also have pacemaker activity and can therefore spontaneously generate an action potential. However, these cells usually do not depolarize spontaneously, simply because action potential production in the SAN is faster. This means that before the AVN or Purkinje fibres reach the threshold potential for an action potential, they are depolarized by

4988-400: The importance of the ions within the T-tubules (particularly calcium in cardiac muscle), it is very important that these concentrations remain relatively constant. As the T-tubules are very thin, they essentially trap the ions. This is important as, regardless of the ion concentrations elsewhere in the cell, T-tubules still have enough calcium ions to permit muscle contraction. Therefore, even if

5074-432: The initial stimulus is not strong enough, and the threshold potential is not reached, the rapid sodium channels will not be activated and an action potential will not be produced; this is known as the all-or-none law . The influx of calcium ions (Ca ) through L-type calcium channels also constitutes a minor part of the depolarisation effect. The slope of phase 0 on the action potential waveform (see figure 2) represents

5160-417: The inner side of the membrane compared to the outer side, and the membrane is described as being polarised. During an action potential, positively charged particles (predominantly sodium and calcium ions) flow across the membrane from the outside to the inside. This reverses the normal imbalance of charged particles and is referred to as depolarization . One region of membrane depolarizes adjacent regions, and

5246-416: The intracellular calcium is pumped out, which was responsible for cardiac myocyte contraction. Once this is lost, the contraction stops and the heart muscles relax. In the sinoatrial node, this phase is also due to the closure of the L-type calcium channels, preventing inward flux of Ca and the opening of the rapid delayed rectifier potassium channels (I Kr ). Cardiac cells have two refractory periods ,

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5332-405: The intracellular calcium store known as the sarcoplasmic reticulum in specific regions referred to as terminal cisternae. The association of the T-tubule with a terminal cisterna is known as a diad . In skeletal muscle cells, T-tubules are three to four times narrower than those in cardiac muscle cells, and are between 20 and 40 nm in diameter. They are typically located at either side of

5418-480: The inwardly rectifying potassium channel. Therefore, the resting membrane potential is mostly equal to K equilibrium potential and can be calculated using the Goldman-Hodgkin-Katz voltage equation . However, pacemaker cells are never at rest. In these cells, phase 4 is also known as the pacemaker potential . During this phase, the membrane potential slowly becomes more positive, until it reaches

5504-474: The maximum rate of voltage change of the cardiac action potential and is known as dV/dt max . In pacemaker cells (e.g. sinoatrial node cells ), however, the increase in membrane voltage is mainly due to activation of L-type calcium channels. These channels are also activated by an increase in voltage, however this time it is either due to the pacemaker potential (phase 4) or an oncoming action potential. The L-type calcium channels are activated more slowly than

5590-484: The membrane potential remaining relatively constant, with K outflux, Cl influx as well as Na /K pumps contributing to repolarisation and Ca influx as well as Na /Ca exchangers contributing to depolarisation. This phase is responsible for the large duration of the action potential and is important in preventing irregular heartbeat (cardiac arrhythmia). There is no plateau phase present in pacemaker action potentials. During phase 3 (the "rapid repolarization" phase) of

5676-451: The membrane, which usually occurs from neighboring cells, through gap junctions. They allow for a rapid flow of sodium into the cell, depolarizing the membrane completely and initiating an action potential. As the membrane potential increases, these channels then close and lock (become inactive). Due to the rapid influx sodium ions (steep phase 0 in action potential waveform) activation and inactivation of these channels happens almost at exactly

5762-440: The movement of specific ions across a membrane. They are said to be selectively permeable. Stimuli, which can either come from outside the cell or from within the cell, can include the binding of a specific molecule to a receptor on the channel (also known as ligand-gated ion channels ) or a change in membrane potential around the channel, detected by a sensor (also known as voltage-gated ion channels ) and can act to open or close

5848-406: The myosin strip, at the junction of overlap (A-I junction) between the A and I bands. T-tubules in skeletal muscle are associated with two terminal cisternae , known as a triad . The shape of the T-tubule system is produced and maintained by a variety of proteins. The protein amphiphysin-2 is encoded by the gene BIN1 and is responsible for forming the structure of the T-tubule and ensuring that

5934-480: The oncoming impulse from the SAN This is called "overdrive suppression". Pacemaker activity of these cells is vital, as it means that if the SAN were to fail, then the heart could continue to beat, albeit at a lower rate (AVN= 40-60 beats per minute, Purkinje fibres = 20-40 beats per minute). These pacemakers will keep a patient alive until the emergency team arrives. An example of premature ventricular contraction

6020-426: The original chemical gradients, that is to force the sodium and calcium which previously flowed into the cell out of it, and the potassium which previously flowed out of the cell back into it (though as the potassium is mostly at the electrochemical equilibrium, its chemical gradient will naturally reequilibrate itself opposite to the electrical gradient, without the need for an active transport mechanism). For example,

6106-422: The passage of both K and Na into the cell. Due to their unusual property of being activated by very negative membrane potentials, the movement of ions through the HCN channels is referred to as the funny current (see below). Another hypothesis regarding the pacemaker potential is the 'calcium clock'. Calcium is released from the sarcoplasmic reticulum within the cell. This calcium then increases activation of

6192-616: The passage of both Na and K into the cell (which is a movement known as a funny current, I f ). These poorly selective, cation (positively charged ions) channels conduct more current as the membrane potential becomes more negative (hyperpolarised). The activity of these channels in the SAN cells causes the membrane potential to depolarise slowly and so they are thought to be responsible for the pacemaker potential. Sympathetic nerves directly affect these channels, resulting in an increased heart rate (see below). These sodium channels are voltage-dependent, opening rapidly due to depolarization of

6278-453: The plateau phase of the action potential, and are named based on the speed at which they activate: slowly activating I Ks , rapidly activating I Kr and ultra-rapidly activating I Kur . There are two voltage-gated calcium channels within cardiac muscle: L-type calcium channels ('L' for Long-lasting) and T-type calcium channels ('T' for Transient, i.e. short). L-type channels are more common and are most densely populated within

6364-492: The relative concentrations of these ions and the voltage across the cell membrane (the electrochemical gradient ). The calcium ATPase removes calcium from the cell actively, using energy derived from adenosine triphosphate (ATP). In order to study T-tubule function, T-tubules can be artificially uncoupled from the surface membrane using a technique known as detubulation . Chemicals such as glycerol or formamide (for skeletal and cardiac muscle respectively) can be added to

6450-424: The resulting wave of depolarization then spreads along the cell membrane. The polarization of the membrane is restored as potassium ions flow back across the membrane from the inside to the outside of the cell. In cardiac muscle cells, as the action potential passes down the T-tubules it activates L-type calcium channels in the T-tubular membrane. Activation of the L-type calcium channel allows calcium to pass into

6536-452: The same constituents as the solution that surrounds the cell (the extracellular fluid). Rather than being just a passive connecting tube, the membrane that forms T-tubules is highly active, being studded with proteins including L-type calcium channels , sodium-calcium exchangers , calcium ATPases and Beta adrenoceptors . T-tubules are found in both atrial and ventricular cardiac muscle cells ( cardiomyocytes ), in which they develop in

6622-454: The same function in muscle cells as the plasma membrane does in other eukaryote cells. It acts as a barrier between the extracellular and intracellular compartments, defining the individual muscle fibre from its surroundings. The lipid nature of the membrane allows it to separate the fluids of the intra- and extracellular compartments, since it is only selectively permeable to water through aquaporin channels. As in other cells, this allows for

6708-406: The same time. During the inactivation state, Na cannot pass through (absolute refractory period). However they begin to recover from inactivation as the membrane potential becomes more negative (relative refractory period). The two main types of potassium channels in cardiac cells are inward rectifiers and voltage-gated potassium channels. Inwardly rectifying potassium channels (K ir) favour

6794-414: The sarcolemma at one end before travelling deep within the cell, forming a network of tubules with sections running both perpendicular (transverse) to and parallel (axially) to the sarcolemma. Due to this complex orientation, some refer to T-tubules as the transverse-axial tubular system. The inside or lumen of the T-tubule is open at the cell surface, meaning that the T-tubule is filled with fluid containing

6880-475: The sarcoplasmic reticulum, causing the muscle cell to contract. In skeletal muscle cells, however, the L-type calcium channel is directly attached to the ryanodine receptor on the sarcoplasmic reticulum allowing activation of the ryanodine receptor directly without the need for an influx of calcium. The importance of T-tubules is not solely due to their concentration of L-type calcium channels, but lies also within their ability to synchronise calcium release within

6966-418: The sodium channels, therefore, the depolarization slope in the pacemaker action potential waveform is less steep than that in the non-pacemaker action potential waveform. This phase begins with the rapid inactivation of the Na channels by the inner gate (inactivation gate), reducing the movement of sodium into the cell. At the same time potassium channels (called I to1 ) open and close rapidly, allowing for

7052-419: The states of sodium and potassium channels . The rapid depolarization of the cell, during phase 0, causes the membrane potential to approach sodium's equilibrium potential (i.e. the membrane potential at which sodium is no longer drawn into or out of the cell). As the membrane potential becomes more positive, the sodium channels then close and lock, this is known as the "inactivated" state. During this state

7138-441: The transient out potassium current I to1 . This current has two components. Both components activate rapidly, but I to,fast inactivates more rapidly than I to, slow . These currents contribute to the early repolarization phase (phase 1) of the action potential. Another form of voltage-gated potassium channels are the delayed rectifier potassium channels. These channels carry potassium currents which are responsible for

7224-504: The types of ion channels expressed and mechanisms by which they are activated results in differences in the configuration of the action potential waveform, as shown in figure 2. Cardiac automaticity also known as autorhythmicity , is the property of the specialized conductive muscle cells of the heart to generate spontaneous cardiac action potentials. Automaticity can be normal or abnormal, caused by temporary ion channel characteristic changes such as certain medication usage, or in

7310-517: The use of interval training . Sarcolemma The sarcolemma ( sarco (from sarx ) from Greek; flesh, and lemma from Greek; sheath), also called the myolemma , is the cell membrane surrounding a skeletal muscle fibre or a cardiomyocyte . It consists of a lipid bilayer and a thin outer coat of polysaccharide material ( glycocalyx ) that contacts the basement membrane . The basement membrane contains numerous thin collagen fibrils and specialized proteins such as laminin that provide

7396-451: The voltage-gated sodium ion channels have recovered and the voltage-gated potassium ion channels remain open, it is possible to initiate another action potential if the stimulus is stronger than a stimulus which can fire an action potential when the membrane is at rest. Gap junctions allow the action potential to be transferred from one cell to the next (they are said to electrically couple neighbouring cardiac cells ). They are made from

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