A neuromuscular junction is a chemical synapse formed by the contact between a motor neuron and a muscle fiber. It is at the neuromuscular junction that a motor neuron is able to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to function—and just to maintain muscle tone, avoiding atrophy. Synaptic transmission at the neuromuscular junction begins when an action potential reaches the presynaptic terminal of a motor neuron, which activates voltage-dependent calcium channels to allow calcium ions to enter the neuron. Calcium ions bind to sensor proteins on synaptic vesicles, triggering vesicle fusion with the cell membrane and subsequent neurotransmitter release from the motor neuron into the synaptic cleft. In vertebrates, motor neurons release acetylcholine, a small molecule neurotransmitter, which diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors on the cell membrane of the muscle fiber known as the sarcolemma. NAChRs are ionotropic receptors.
The binding of ACh to the receptor can depolarize the muscle fiber, causing a cascade that results in muscle contraction. Neuromuscular junction diseases can be of autoimmune origin. Genetic disorders, such as Duchenne muscular dystrophy, can arise from mutated structural proteins that comprise the neuromuscular junction, whereas autoimmune diseases, such as myasthenia gravis, occur when antibodies are produced against nicotinic acetylcholine receptors on the sarcolemma. At the neuromuscular junction presynaptic motor axons terminate 30 nanometers from the cell membrane or sarcolemma of a muscle fiber; the sarcolemma at the junction has invaginations called postjunctional folds, which increase its surface area facing the synaptic cleft. These postjunctional folds form the motor endplate, studded with nicotinic acetylcholine receptors at a density of 10,000 receptors/micrometer2; the presynaptic axons terminate in bulges called terminal boutons that project toward the postjunctional folds of the sarcolemma.
In the frog each motor nerve terminal contains about 300,000 vesicles, with an average diameter of 0.05 micrometers. The vesicles contain acetylcholine; some of these vesicles are gathered into groups of fifty, positioned at active zones close to the nerve membrane. Active zones are about 1 micrometer apart; the 30 nanometer cleft between nerve ending and endplate contains a meshwork of acetylcholinesterase at a density of 2,600 enzyme molecules/micrometer2, held in place by the structural proteins dystrophin and rapsyn. Present is the receptor tyrosine kinase protein MuSK, a signaling protein involved in the development of the neuromuscular junction, held in place by rapsyn. About once every second in a resting junction randomly one of the synaptic vesicles fuses with the presynaptic neuron's cell membrane in a process mediated by SNARE proteins. Fusion results in the emptying of the vesicle's contents of 7000-10,000 acetylcholine molecules into the synaptic cleft, a process known as exocytosis.
Exocytosis releases acetylcholine in packets that are called quanta. The acetylcholine quantum diffuses through the acetylcholinesterase meshwork, where the high local transmitter concentration occupies all of the binding sites on the enzyme in its path; the acetylcholine that reaches the endplate activates ~2,000 acetylcholine receptors, opening their ion channels which permits sodium ions to move into the endplate producing a depolarization of ~0.5 mV known as a miniature endplate potential. By the time the acetylcholine is released from the receptors the acetylcholinesterase has destroyed its bound ACh, which takes about ~0.16 ms, hence is available to destroy the ACh released from the receptors. When the motor nerve is stimulated there is a delay of only 0.5 to 0.8 msec between the arrival of the nerve impulse in the motor nerve terminals and the first response of the endplate The arrival of the motor nerve action potential at the presynaptic neuron terminal opens voltage-dependent calcium channels and Ca2+ ions flow from the extracellular fluid into the presynaptic neuron's cytosol.
This influx of Ca2+ causes several hundred neurotransmitter-containing vesicles to fuse with the presynaptic neuron's cell membrane through SNARE proteins to release their acetylcholine quanta by exocytosis. The endplate depolarization by the released acetylcholine is called an endplate potential; the EPP is accomplished when ACh binds the nicotinic acetylcholine receptors at the motor end plate, causes an influx of sodium ions. This influx of sodium ions generates the EPP, triggers an action potential which travels along the sarcolemma and into the muscle fiber via the transverse tubules by means of voltage-gated sodium channels; the conduction of action potentials along the transverse tubules stimulates the opening of voltage-gated Ca2+ channels which are mechanically coupled to Ca2+ release channels in the sarcoplasmic reticulum. The Ca2+ diffuses out of the sarcoplasmic reticulum to the myofibrils so it can stimulate contraction; the endplate potential is thus responsible for setting up an action potential in the muscle fiber which triggers muscle contraction.
The transmission from nerve to muscle is so rapid because each quantum of acetylcholine reaches the endplate in millimolar concentrations, high enough to combine with a receptor with a low affinity, which swiftly releases the bound transmitter. Acetylcholine is a neurotransmitter synthesized from dietary choline and acetyl-CoA, is involved in the stimulation of muscle tissue in vertebrates as well as i
Potassium channels are the most distributed type of ion channel and are found in all living organisms. They form. Furthermore, potassium channels are found in most cell types and control a wide variety of cell functions. Potassium channels function to conduct potassium ions down their electrochemical gradient, doing so both and selectively. Biologically, these channels act to reset the resting potential in many cells. In excitable cells, such as neurons, the delayed counterflow of potassium ions shapes the action potential. By contributing to the regulation of the action potential duration in cardiac muscle, malfunction of potassium channels may cause life-threatening arrhythmias. Potassium channels may be involved in maintaining vascular tone, they regulate cellular processes such as the secretion of hormones so their malfunction can lead to diseases. There are four major classes of potassium channels: Calcium-activated potassium channel - open in response to the presence of calcium ions or other signalling molecules.
Inwardly rectifying potassium channel - passes current more in the inward direction. Tandem pore domain potassium channel - are constitutively open or possess high basal activation, such as the "resting potassium channels" or "leak channels" that set the negative membrane potential of neurons. Voltage-gated potassium channel - are voltage-gated ion channels that open or close in response to changes in the transmembrane voltage; the following table contains a comparison of the major classes of potassium channels with representative examples. Potassium channels have a tetrameric structure in which four identical protein subunits associate to form a fourfold symmetric complex arranged around a central ion conducting pore. Alternatively four related but not identical protein subunits may associate to form heterotetrameric complexes with pseudo C4 symmetry. All potassium channel subunits have a distinctive pore-loop structure that lines the top of the pore and is responsible for potassium selective permeability.
There are over 80 mammalian genes. However potassium channels found in bacteria are amongst the most studied of ion channels, in terms of their molecular structure. Using X-ray crystallography, profound insights have been gained into how potassium ions pass through these channels and why sodium ions do not; the 2003 Nobel Prize for Chemistry was awarded to Rod MacKinnon for his pioneering work in this area. Potassium ion channels remove the hydration shell from the ion when it enters the selectivity filter; the selectivity filter is formed by a five residue sequence, TVGYG, termed the signature sequence, within each of the four subunits. This signature sequence is within a loop between the pore helix and TM2/6 termed the P-loop; this signature sequence is conserved, with the exception that a valine residue in prokaryotic potassium channels is substituted with an isoleucine residue in eukaryotic channels. This sequence adopts a unique main chain structure, structurally analogous to a nest protein structural motif.
The four sets of electronegative carbonyl oxygen atoms are aligned toward the center of the filter pore and form a square anti-prism similar to a water-solvating shell around each potassium binding site. The distance between the carbonyl oxygens and potassium ions in the binding sites of the selectivity filter is the same as between water oxygens in the first hydration shell and a potassium ion in water solution, providing an energetically-favorable route for de-solvation of the ions; this width appears to be maintained by hydrogen bonding and van der Waals forces within a sheet of aromatic amino acid residues surrounding the selectivity filter. The selectivity filter opens towards the extracellular solution, exposing four carbonyl oxygens in a glycine residue; the next residue toward the extracellular side of the protein is the negatively charged Asp80. This residue together with the five filter residues form the pore that connects the water-filled cavity in the center of the protein with the extracellular solution.
The mechanism of potassium channel selectivity remains under continued debate. The carbonyl oxygens are electro-negative and cation-attractive; the filter can accommodate potassium ions at 4 sites labelled S1 to S4 starting at the extracellular side. In addition, one ion can bind in the cavity at a site called SC or one or more ions at the extracellular side at more or less well-defined sites called S0 or Sext. Several different occupancies of these sites are possible. Since the X-ray structures are averages over many molecules, it is, not possible to deduce the actual occupancies directly from such a structure. In general, there is some disadvantage due to electrostatic repulsion to have two neighboring sites occupied by ions. Proposals for the mechanism of selectivity have been made based on molecular dynamics simulations, toy models of ion binding, thermodynamic calculations, topological considerations, structural differences between selective and non-selective channels; the mechanism for ion translocation in KcsA has been studied extensively by theoretical calculations and simulation.
The prediction of an ion conduction mechanism in which the two doubly occupied states and play an essential role has been affirmed by both techniques. MD simulations
Blood plasma is a yellowish liquid component of blood that holds the blood cells in whole blood in suspension. In other words, it is the liquid part of the blood that carries cells and proteins throughout the body, it makes up about 55% of the body's total blood volume. It is the intravascular fluid part of extracellular fluid, it is water, contains dissolved proteins, clotting factors, hormones, carbon dioxide and oxygen. It plays a vital role in an intravascular osmotic effect that keeps electrolyte concentration balanced and protects the body from infection and other blood disorders. Blood plasma is separated from the blood by spinning a tube of fresh blood containing an anticoagulant in a centrifuge until the blood cells fall to the bottom of the tube; the blood plasma is poured or drawn off. Blood plasma has a density of 1025 kg/m3, or 1.025 g/ml. Blood serum is blood plasma without clotting factors. Plasmapheresis is a medical therapy that involves blood plasma extraction and reintegration.
Fresh frozen plasma is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. It is of critical importance in the treatment of many types of trauma which result in blood loss, is therefore kept stocked universally in all medical facilities capable of treating trauma or that pose a risk of patient blood loss such as surgical suite facilities. Blood plasma volume may be expanded by or drained to extravascular fluid when there are changes in Starling forces across capillary walls. For example, when blood pressure drops in circulatory shock, Starling forces drive fluid into the interstitium, causing third spacing. Standing still for a prolonged period will cause an increase in transcapillary hydrostatic pressure; as a result 12% of blood plasma volume will cross into the extravascular compartment. This causes an increase in hematocrit, serum total protein, blood viscosity and, as a result of increased concentration of coagulation factors, it causes orthostatic hypercoagulability.
Plasma was well-known when described by William Harvey in de Mortu Cordis in 1628, but knowledge of it extends as far back as Vesalius.. The discovery of fibrinogen by William Henson in ca 1770 made it easier to study plasma, as ordinarily, upon coming in contact with a foreign surface – something other than vascular endothelium – clotting factors become activated and clotting proceeds trapping RBCs etc in the plasma and preventing separation of plasma from the blood. Adding citrate and other anticoagulants is a recent advance. Note that, upon formation of a clot, the remaining clear fluid is Serum, plasma without the clotting factors; the use of blood plasma as a substitute for whole blood and for transfusion purposes was proposed in March 1918, in the correspondence columns of the British Medical Journal, by Gordon R. Ward. "Dried plasmas" in powder or strips of material format were developed and first used in World War II. Prior to the United States' involvement in the war, liquid plasma and whole blood were used.
The "Blood for Britain" program during the early 1940s was quite successful based on Charles Drew's contribution. A large project began in August 1940 to collect blood in New York City hospitals for the export of plasma to Britain. Drew was appointed medical supervisor of the "Plasma for Britain" project, his notable contribution at this time was to transform the test tube methods of many blood researchers into the first successful mass production techniques. The decision was made to develop a dried plasma package for the armed forces as it would reduce breakage and make the transportation and storage much simpler; the resulting dried. One bottle contained enough distilled water to reconstitute the dried plasma contained within the other bottle. In about three minutes, the plasma could stay fresh for around four hours; the Blood for Britain program operated for five months, with total collections of 15,000 people donating blood, with over 5,500 vials of blood plasma. Following the "Plasma for Britain" invention, Drew was named director of the Red Cross blood bank and assistant director of the National Research Council, in charge of blood collection for the United States Army and Navy.
Drew argued against the armed forces directive that blood/plasma was to be separated by the race of the donor. Drew insisted that there was no racial difference in human blood and that the policy would lead to needless deaths as soldiers and sailors were required to wait for "same race" blood. By the end of the war the American Red Cross had provided enough blood for over six million plasma packages. Most of the surplus plasma was returned to the United States for civilian use. Serum albumin replaced dried plasma for combat use during the Korean War. Plasma as a blood product prepared from blood donations is used in blood transfusions as fresh frozen plasma or plasma Frozen Within 24 Hours After Phlebotomy; when donating whole blood or packed red blood cell transfusions, O- is the most desirable and is considered a "universal donor," since it has neither A nor B antigens and can be safely transfused to most recipients. Type AB+ is the "universal recipient" type for PRBC donations. However, for plasma the situation is somewhat reverse
An antibody known as an immunoglobulin, is a large, Y-shaped protein produced by plasma cells, used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding variable region; each tip of the "Y" of an antibody contains a paratope, specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly. Depending on the antigen, the binding may impede the biological process causing the disease or may activate macrophages to destroy the foreign substance; the ability of an antibody to communicate with the other components of the immune system is mediated via its Fc region, which contains a conserved glycosylation site involved in these interactions. The production of antibodies is the main function of the humoral immune system.
Antibodies are secreted by B cells of the adaptive immune system by differentiated B cells called plasma cells. Antibodies can occur in two physical forms, a soluble form, secreted from the cell to be free in the blood plasma, a membrane-bound form, attached to the surface of a B cell and is referred to as the B-cell receptor; the BCR is found only on the surface of B cells and facilitates the activation of these cells and their subsequent differentiation into either antibody factories called plasma cells or memory B cells that will survive in the body and remember that same antigen so the B cells can respond faster upon future exposure. In most cases, interaction of the B cell with a T helper cell is necessary to produce full activation of the B cell and, antibody generation following antigen binding. Soluble antibodies are released into the blood and tissue fluids, as well as many secretions to continue to survey for invading microorganisms. Antibodies are glycoproteins belonging to the immunoglobulin superfamily.
They constitute most of the gamma globulin fraction of the blood proteins. They are made of basic structural units—each with two large heavy chains and two small light chains. There are several different types of antibody heavy chains that define the five different types of crystallisable fragments that may be attached to the antigen-binding fragments; the five different types of Fc regions allow antibodies to be grouped into five isotypes. Each Fc region of a particular antibody isotype is able to bind to its specific Fc Receptor, thus allowing the antigen-antibody complex to mediate different roles depending on which FcR it binds; the ability of an antibody to bind to its corresponding FcR is further modulated by the structure of the glycan present at conserved sites within its Fc region. The ability of antibodies to bind to FcRs helps to direct the appropriate immune response for each different type of foreign object they encounter. For example, IgE is responsible for an allergic response consisting of mast cell degranulation and histamine release.
IgE's Fab paratope binds to allergic antigen, for example house dust mite particles, while its Fc region binds to Fc receptor ε. The allergen-IgE-FcRε interaction mediates allergic signal transduction to induce conditions such as asthma. Though the general structure of all antibodies is similar, a small region at the tip of the protein is variable, allowing millions of antibodies with different tip structures, or antigen-binding sites, to exist; this region is known as the hypervariable region. Each of these variants can bind to a different antigen; this enormous diversity of antibody paratopes on the antigen-binding fragments allows the immune system to recognize an wide variety of antigens. The large and diverse population of antibody paratope is generated by random recombination events of a set of gene segments that encode different antigen-binding sites, followed by random mutations in this area of the antibody gene, which create further diversity; this recombinational process that produces clonal antibody paratope diversity is called VJ or VJ recombination.
The antibody paratope is polygenic, made up of three genes, V, D, J. Each paratope locus is polymorphic, such that during antibody production, one allele of V, one of D, one of J is chosen; these gene segments are joined together using random genetic recombination to produce the paratope. The regions where the genes are randomly recombined together is the hyper variable region used to recognise different antigens on a clonal basis. Antibody genes re-organize in a process called class switching that changes the one type of heavy chain Fc fragment to another, creating a different isotype of the antibody that retains the antigen-specific variable region; this allows a single antibody to be used by different types of Fc receptors, expressed on different parts of the immune system. The first use of the term "antibody" occurred in a text by Paul Ehrlich; the term Antikörper appears in the conclusion of his article "Experimental Studies on Immunity", published in October 1891, which states that, "if two substances give rise to two different Antikörper they themselves must be different".
However, the term was not accepted and several other terms for antibody were proposed.
A motor nerve is a nerve located in the central nervous system the spinal cord, that sends motor signals from the CNS to the muscles of the body. This is different from the motor neuron, which includes a cell body and branching of dendrites, while the nerve is made up of a bundle of axons. Motor nerves act as efferent nerves which carry information out from the CNS, as opposed to afferent nerves, which send signals from sensory receptors in the periphery to the CNS. There are nerves that serve as both sensory and motor nerves called mixed nerves. Motor nerve fibers transduce signals from the CNS to peripheral neurons of proximal muscle tissue. Motor nerve axon terminals innervate skeletal and smooth muscle, as they are involved in muscle control. Motor nerves tend to be rich in Acetylcholine vesicles because the motor nerve, a bundle of motor nerve axons that deliver motor signals and signal for movement and motor control. Calcium vesicles reside in the axon terminals of the motor nerve bundles.
The high calcium concentration outside of presynaptic motor nerves increases the size of EPPs. Within motor nerves, each axon is wrapped by the endoneurium, a layer of connective tissue that surrounds the myelin sheath. Bundles of axons are called fascicles. All of the fascicles wrapped in the perineurium are wound together and wrapped by a final layer of connective tissue known as the epineurium; these protective tissues defend nerves from injury and help to maintain nerve function. Layers of connective tissue maintain the rate. Most motor pathways originate in the motor cortex of the brain. Signals run down the brainstem and spinal cord ipsilaterally, on the same side, exit the spinal cord at the ventral horn of the spinal cord on either side. Motor nerves communicate with the muscle cells they innervate through motor neurons once they exit the spinal cord. Motor nerves can vary based on the subtype of motor neuron they are associate with. Alpha motor neurons target extrafusal muscle fibers; the motor nerves associated with these neurons innervate extrafusal skeletal muscle fibers and are responsible for muscle contraction.
These nerve fibers have the largest diameter of the motor neurons and require the highest conduction velocity of the three types. Beta motor neurons innervate intrafusal fibers of muscle spindles; these nerves are responsible for signaling slow twitch muscle fibers. Gamma motor neurons, unlike alpha motor neurons, are not directly involved in muscle contraction; the nerves associated with these neurons do not send signals that directly adjust the shortening or lengthening of muscle fibers. However, these nerves are important in keeping muscle spindles taut. Motor neural degeneration is the progressive weakening of neural tissues and connections in the nervous system. Muscles begin to weaken as there are no longer any motor nerves or pathways that allows for muscle innervation. Motor neuron diseases can be a result of environmental factors; the exact causes remain unclear, however many experts believe that toxic and environmental factors play a large role. There are problems with neuroregeneration due to many sources, both external.
There is a weak regenerative ability of nerves and new nerve cells cannot be made. The outside environment can play a role in nerve regeneration. Neural stem cells, are able to differentiate into many different types of nerve cells; this is one way. NSC transplant into damaged areas leads to the cells differentiating into astrocytes which assists the surrounding neurons. Schwann cells have the ability to regenerate, but the capacity that these cells can repair nerve cells declines as time goes on as well as distance the Schwann cells are from site of damage
Voltage-gated potassium channel
Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state. Alpha subunits form the actual conductance pore. Based on sequence homology of the hydrophobic transmembrane cores, the alpha subunits of voltage-gated potassium channels are grouped into 12 classes; these are labeled Kvα1-12. The following is a list of the 40 known human voltage-gated potassium channel alpha subunits grouped first according to function and subgrouped according to the Kv sequence homology classification scheme: inactivating or non-inactivating Kvα1.x - Shaker-related: Kv1.1, Kv1.2, Kv1.3, Kv1.5, Kv1.6, Kv1.7, Kv1.8 Kvα2.x - Shab-related: Kv2.1, Kv2.2 Kvα3.x - Shaw-related: Kv3.1, Kv3.2 Kvα7.x: Kv7.1 - KvLQT1, Kv7.2, Kv7.3, Kv7.4, Kv7.5 Kvα10.x: Kv10.1 inactivating Kvα1.x - Shaker-related: Kv1.4 Kvα3.x - Shaw-related: Kv3.3, Kv3.4 Kvα4.x - Shal-related: Kv4.1, Kv4.2, Kv4.3 Kvα10.x: Kv10.2 Passes current more in the inward direction.
Kvα11.x - ether-a-go-go potassium channels: Kv11.1 - hERG, Kv11.2, Kv11.3 Kvα12.x: Kv12.1, Kv12.2, Kv12.3 Unable to form functional channels as homotetramers but instead heterotetramerize with Kvα2 family members to form conductive channels. Kvα5.x: Kv5.1 Kvα6.x: Kv6.1, Kv6.2, Kv6.3, Kv6.4 Kvα8.x: Kv8.1, Kv8.2 Kvα9.x: Kv9.1, Kv9.2, Kv9.3 Beta subunits are auxiliary proteins that associate with alpha subunits, sometimes in a α4β4 stoichiometry. These subunits rather modulate the activity of Kv channels. Kvβ1 Kvβ2 Kvβ3 minK MiRP1 MiRP2 MiRP3 KCNE1-like KCNIP1 KCNIP2 KCNIP3 KCNIP4 Proteins minK and MiRP1 are putative hERG beta subunits; the voltage-gated K+ channels that provide the outward currents of action potentials have similarities to bacterial K+ channels. These channels have been studied by X-ray diffraction, allowing determination of structural features at atomic resolution; the function of these channels is explored by electrophysiological studies. Genetic approaches include screening for behavioral changes in animals with mutations in K+ channel genes.
Such genetic methods allowed the genetic identification of the "Shaker" K+ channel gene in Drosophila before ion channel gene sequences were well known. Study of the altered properties of voltage-gated K+ channel proteins produced by mutated genes has helped reveal the functional roles of K+ channel protein domains and individual amino acids within their structures. Vertebrate voltage-gated K+ channels are tetramers of four identical subunits arranged as a ring, each contributing to the wall of the trans-membrane K+ pore; each subunit is composed of six membrane spanning hydrophobic α-helical sequences, as well as a voltage sensor in S4. The intracellular side of the membrane contains both carboxy termini; the high resolution crystallographic structure of the rat Kvα1.2/β2 channel has been solved, refined in a lipid membrane-like environment. Voltage-gated K+ channels are selective for K+ over other cations such as Na+. There is a selectivity filter at the narrowest part of the transmembrane pore.
Channel mutation studies have revealed the parts of the subunits that are essential for ion selectivity. They include the amino acid sequence or typical to the selectivity filter of voltage-gated K+ channels; as K+ passes through the pore, interactions between potassium ions and water molecules are prevented and the K+ interacts with specific atomic components of the Thr-Val-Gly--Gly sequences from the four channel subunits. It may seem counterintuitive that a channel should allow potassium ions but not the smaller sodium ions through; however in an aqueous environment and sodium cations are solvated by water molecules. When moving through the selectivity filter of the potassium channel, the water-K+ interactions are replaced by interactions between K+ and carbonyl groups of the channel protein; the diameter of the selectivity filter is ideal for the potassium cation, but too big for the smaller sodium cation. Hence the potassium cations are well "solvated" by the protein carbonyl groups, but these same carbonyl groups are too far apart to adequately solvate the sodium cation.
Hence, the passage of potassium cations through this selectivity filter is favored over sodium cations. The structure of the mammalian voltage-gated K+ channel has been used to explain its ability to respond to the voltage across the membrane. Upon opening of the channel, conformational changes in the voltage-sensor domains result in the transfer of 12-13 elementary charges across the membrane electric field; this charge transfer is measured as a transient capacitive current that precedes opening of the channel. Several charged residues of the VSD, in particular four arginine residues located at every third position on the S4 segment, are known to move across the transmembrane field and contribute to the gating charge; the position of these arginines, known as gating arginines, are conserved in all voltage-gated potassium, sodium, or calcium channels. However, the extent of their movement and their displacement across the transmembrane potential has been subjec