1.
Action potential
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In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of cells, called excitable cells, which include neurons, muscle cells. In other types of cells, their function is to activate intracellular processes. In muscle cells, for example, a potential is the first step in the chain of events leading to contraction. In beta cells of the pancreas, they provoke release of insulin, action potentials in neurons are also known as nerve impulses or spikes, and the temporal sequence of action potentials generated by a neuron is called its spike train. A neuron that emits an action potential is often said to fire, action potentials are generated by special types of voltage-gated ion channels embedded in a cells plasma membrane. When the channels open they allow a flow of sodium ions, which changes the electrochemical gradient. This then causes more channels to open, producing an electric current across the cell membrane. The process proceeds explosively until all of the ion channels are open. The rapid influx of ions causes the polarity of the plasma membrane to reverse. As the sodium channels close, sodium ions can no longer enter the neuron, potassium channels are then activated, and there is an outward current of potassium ions, returning the electrochemical gradient to the resting state. After an action potential has occurred, there is a transient negative shift, in animal cells, there are two primary types of action potentials. One type is generated by voltage-gated sodium channels, the other by voltage-gated calcium channels, sodium-based action potentials usually last for under one millisecond, whereas calcium-based action potentials may last for 100 milliseconds or longer. In some types of neurons, slow calcium spikes provide the force for a long burst of rapidly emitted sodium spikes. In cardiac muscle cells, on the hand, an initial fast sodium spike provides a primer to provoke the rapid onset of a calcium spike. Nearly all cell membranes in animals, plants and fungi maintain a voltage difference between the exterior and interior of the cell, called the membrane potential. A typical voltage across a cell membrane is –70 mV. In most types of cells the membrane potential usually stays fairly constant, some types of cells, however, are electrically active in the sense that their voltages fluctuate over time
2.
Cardiac muscle
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Cardiac muscle is an involuntary, striated muscle that is found in the walls and histological foundation of the heart, specifically the myocardium. Cardiac muscle is one of three types of muscle, the others being skeletal and smooth muscle. These three types of all form in the process of myogenesis. The cells that constitute cardiac muscle, called cardiomyocytes or myocardiocytes, predominantly contain only one nucleus, the myocardium is the muscle tissue of the heart, and forms a thick middle layer between the outer epicardium layer and the inner endocardium layer. Coordinated contractions of cardiac cells in the heart pump blood out of the atria and ventricles to the blood vessels of the left/body/systemic. This complex mechanism illustrates systole of the heart, Cardiac muscle cells, unlike most other tissues in the body, rely on an available blood and electrical supply to deliver oxygen and nutrients and remove waste products such as carbon dioxide. The coronary arteries help fulfill this function, Cardiac muscle has cross striations formed by rotating segments of thick and thin protein filaments. Like skeletal muscle, the structural proteins of cardiac muscle are myosin and actin. However, in contrast to skeletal muscle, cardiac muscle cells are typically branch-like instead of linear, another histological difference between cardiac muscle and skeletal muscle is that the T-tubules in the cardiac muscle are bigger and wider and track laterally to the Z-discs. There are fewer T-tubules in comparison with skeletal muscle, the diad is a structure in the cardiac myocyte located at the sarcomere Z-line. It is composed of a single T-tubule paired with a terminal cisterna of the sarcoplasmic reticulum, the diad plays an important role in excitation-contraction coupling by juxtaposing an inlet for the action potential near a source of Ca2+ ions. This way, the wave of depolarization can be coupled to calcium-mediated cardiac muscle contraction via the sliding filament mechanism, Cardiac muscle forms these instead of the triads formed between the sarcoplasmic reticulum in skeletal muscle and T-tubules. T-tubules play critical role in excitation-contraction coupling, recently, the action potentials of T-tubules were recorded optically by Guixue Bu et al. There is a syncytium and a ventricular syncytium that are connected by cardiac connection fibres. Electrical resistance through intercalated discs is very low, thus allowing free diffusion of ions, the ease of ion movement along cardiac muscle fibers axes is such that action potentials are able to travel from one cardiac muscle cell to the next, facing only slight resistance. Each syncytium obeys the all or none law, intercalated discs are complex adhering structures that connect the single cardiomyocytes to an electrochemical syncytium. The discs are responsible mainly for force transmission during muscle contraction, intercalated discs consist of three different types of cell-cell junctions, the actin filament anchoring adherens junctions, the intermediate filament anchoring desmosomes, and gap junctions. They allow action potentials to spread between cells by permitting the passage of ions between cells, producing depolarization of the heart muscle
3.
Depolarization
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In biology, depolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell. Depolarization is essential to the function of cells, communication between cells, and the overall physiology of an organism. Most cells in higher organisms maintain an environment that is negatively charged relative to the cells exterior. This difference in charge is called the membrane potential. In the process of depolarization, the internal charge of the cell temporarily becomes more positive. This shift from a negative to a more positive membrane potential occurs during several processes, during an action potential, the depolarization is so large that the potential difference across the cell membrane briefly reverses polarity, with the inside of the cell becoming positively charged. The change in charge typically occurs due to an influx of ions into a cell. The opposite of a depolarization is called a hyperpolarization, usage of the term depolarization in biology differs from its use in physics. In physics it refers instead to situations in which any form of polarity changes to a value of zero, the process of depolarization is entirely dependent upon the intrinsic electrical nature of most cells. When a cell is at rest, the cell maintains what is known as a resting potential, the resting potential generated by nearly all cells results in the interior of the cell having a negative charge compared to the exterior of the cell. To maintain this electrical imbalance, microscopic positively and negatively charged particles called ions are transported across the plasma membrane. The resting potential must be established within a cell before the cell can be depolarized, there are many mechanisms by which a cell can establish a resting potential, however there is a typical pattern of generating this resting potential that many cells follow. The cell uses ion channels, ion pumps, and voltage gated ion channels to generate a negative resting potential within the cell, however, the process of generating the resting potential within the cell also creates an environment outside of the cell that favors depolarization. The sodium potassium pump is largely responsible for the optimization of conditions on both the interior and the exterior of the cell for depolarization, additionally, despite the high concentration of positively-charged potassium ions, most cells contain internal components, which accumulate to establish a negative inner-charge. After a cell has established a potential, that cell has the capacity to undergo depolarization. During depolarization, the charge within the cell rapidly shifts from negative to positive, for this rapid change to take place within the interior of the cell, several events must occur along the plasma membrane of the cell as well. While the sodium potassium pump continues to work, the voltage gated ion channels that had closed while the cell was at resting potential have been opened by an electrical stimulus. As the sodium rushes back into the cell the positive sodium ions raise the charge inside the cell from negative to positive, once the interior of the cell becomes positively charged, depolarization of the cell is complete
4.
Hyperpolarization (biology)
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Hyperpolarization is a change in a cells membrane potential that makes it more negative. It is the opposite of a depolarization and it inhibits action potentials by increasing the stimulus required to move the membrane potential to the action potential threshold. Hyperpolarization is often caused by efflux of K+ through K+ channels, on the other hand, influx of cations, e. g. Na+ through Na+ channels or Ca2+ through Ca2+ channels, inhibits hyperpolarization. If a cell has Na+ or Ca2+ currents at rest, then inhibition of those currents will result in a hyperpolarization. This voltage-gated ion channel response is how the state is achieved. In neurons, the cell enters a state of hyperpolarization immediately following the generation of an action potential, while hyperpolarized, the neuron is in a refractory period that lasts roughly 2 milliseconds, during which the neuron is unable to generate subsequent action potentials. Voltage gated ion channels respond to changes in the membrane potential and these channels work by selecting an ion based on electrostatic attraction or repulsion allowing the ion to bind to the channel. This releases water molecules attached to the ion, and the ion passes through the pore, at this voltage the sodium channels begin to inactivate and voltage gated potassium channels begin to open. This combination of closed sodium channels and open potassium channels leads the neuron to become hyperpolarized, the neuron continues to repolarize until the cell reaches approximately –75 mV, which is the reversal potential of potassium ions. At this point the voltage gated potassium channels close and the permeability of the membrane to sodium and potassium allows the neuron to return to its resting potential of –70 mV. HCN channels are activated by hyperpolarization, hyperpolarization is a change in membrane potential, neuroscientists measure it using a technique known as patch clamping. Using this method they are able to record ion currents passing through individual channels and this is done using a glass micropipette, also called a patch pipette, with a 1 micrometer diameter. There is a patch that contains a few ion channels. The membrane currents giving rise to hyperpolarization are either an increase in current or a decrease in inward current. During the afterhyperpolarization period after a potential, the membrane potential is more negative than when the cell is at the resting potential. In the figure to the right, this occurs at approximately 3 to 4 milliseconds on the time scale. The afterhyperpolarization is the time when the potential is hyperpolarized relative to the resting potential. During the rising phase of a potential, the membrane potential changes from negative to positive
5.
Skeletal muscle
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Skeletal muscle is one of three major muscle types, the others being cardiac muscle and smooth muscle. It is a form of striated muscle tissue which is under the control of the somatic nervous system. Most skeletal muscles are attached to bones by bundles of collagen fibers known as tendons, a skeletal muscle refers to multiple bundles of cells called muscle fibers. The fibres and muscles are surrounded by connective tissue layers called fasciae, Muscle fibres, or muscle cells, are formed from the fusion of developmental myoblasts in a process known as myogenesis. Muscle fibres are cylindrical, and have more than one nucleus, Muscle fibers are in turn composed of myofibrils. The myofibrils are composed of actin and myosin filaments, repeated in units called sarcomeres, the sarcomere is responsible for the striated appearance of skeletal muscle, and forms the basic machinery necessary for muscle contraction. Connective tissue is present in all muscles as fascia, Muscle fibres are the individual contractile units within muscle. A single muscle such as the biceps contains many muscle fibres, another group of cells, the myosatellite cells are found between the basement membrane and the sarcolemma of muscle fibers. These cells are normally quiescent but can be activated by exercise or pathology to provide additional myonuclei for muscle growth or repair, development Individual muscle fibers are formed during development from the fusion of several undifferentiated immature cells known as myoblasts into long, cylindrical, multi-nucleated cells. Differentiation into this state is completed before birth with the cells continuing to grow in size thereafter. Microanatomy Skeletal muscle exhibits a distinctive banding pattern when viewed under the due to the arrangement of cytoskeletal elements in the cytoplasm of the muscle fibers. The principal cytoplasmic proteins are myosin and actin which are arranged in a unit called a sarcomere. The interaction of myosin and actin is responsible for muscle contraction, every single organelle and macromolecule of a muscle fiber is arranged to ensure form meets function. The cell membrane is called the sarcolemma with the known as the sarcoplasm. In the sarcoplasm are the myofibrils, the myofibrils are long protein bundles about 1 micrometer in diameter each containing myofilaments. Pressed against the inside of the sarcolemma are the unusual flattened myonuclei, between the myofibrils are the mitochondria. While the muscle fiber does not have a smooth endoplasmic reticulum, the sarcoplasmic reticulum surrounds the myofibrils and holds a reserve of the calcium ions needed to cause a muscle contraction. Periodically, it has dilated end sacs known as terminal cisternae and these cross the muscle fiber from one side to the other
6.
Inhibitory postsynaptic potential
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An inhibitory postsynaptic potential is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. They can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell to cell signalling, inhibitory presynaptic neurons release neurotransmitters that then bind to the postsynaptic receptors, this induces a postsynaptic conductance change as ion channels open or close. An electric current that changes the membrane potential to create a more negative postsynaptic potential is generated. Depolarization can also occur due to an IPSP if the potential is between the resting threshold and the action potential threshold. Another way to look at inhibitory postsynaptic potentials is that they are also a chloride conductance change in the cell because it decreases the driving force. Microelectrodes can be used to measure postsynaptic potentials at either excitatory or inhibitory synapses, IPSPs always want to keep the membrane potential more negative than the action potential threshold and can be seen as a transient hyperpolarization. EPSPs and IPSPs compete with other at numerous synapses of a neuron. Some common neurotransmitters involved in IPSPs are GABA and glycine and this system IPSPs can be temporally summed with subthreshold or suprathreshold EPSPs to reduce the amplitude of the resultant postsynaptic potential. Equivalent EPSPs and IPSPs can cancel each other out when summed, the balance between EPSPs and IPSPs is very important in the integration of electrical information produced by inhibitory and excitatory synapses. The size of the neuron can also affect the inhibitory postsynaptic potential, GABA is a very common neurotransmitter used in IPSPs in the adult mammalian brain and retina. GABA receptors are pentamers most commonly composed of three different subunits, although several other subunits and conformations exist, the open channels are selectively permeable to chloride or potassium ions and allow these ions to pass through the membrane. Glycine molecules and receptors work much in the way in the spinal cord, brain. There are two types of receptors, Ionotropic receptors play an important role in inhibitory postsynaptic potentials. A neurotransmitter binds to the site and opens the ion channel that is made up of a membrane-spanning domain that allows ions to flow across the membrane inside the postsynaptic cell. This type of receptor produces very fast postsynaptic actions within a couple of milliseconds of the presynaptic terminal receiving an action potential and these channels influence the amplitude and time-course of postsynaptic potentials as a whole. Ionotropic GABA receptors are used in binding for various such as barbiturates, steroids. Benzodiazepines bind to the α and δ subunits of GABA receptors in order to improve GABAergic signaling, alcohol also modulates ionotropic GABA receptors. They produce slow postsynaptic responses and can be activated in conjunction with ionotropic receptors to create both fast and slow postsynaptic potentials at one particular synapse, metabotropic GABA receptors, heterodimers of R1 and R2 subunits, use potassium channels instead of chloride
7.
Ligand-gated ion channel
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When a presynaptic neuron is excited, it releases neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron, if these receptors are ligand-gated ion channels, a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory response, or a hyperpolarization. These proteins are composed of at least two different domains, a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location. This modularity has enabled a divide and conquer approach to finding the structure of the proteins, the function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, LICs are classified into three superfamilies which lack evolutionary relationship, cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels. The cys-loop receptors are named after a loop formed by a disulfide bond between two cysteine residues in the N terminal extracellular domain. Because of this extracellular N-terminal ligand-binding domain, they exhibit receptor specificity for acetylcholine, serotonin, glycine, glutamate, the receptors are subdivided with respect to the type of ion that they conduct and further into families defined by the endogenous ligand. Some also contain an intracellular domain like shown in the image, the prototypic ligand-gated ion channel is the nicotinic acetylcholine receptor. It consists of a pentamer of protein subunits, with two binding sites for acetylcholine and this pore allows Na+ ions to flow down their electrochemical gradient into the cell. With a sufficient number of opening at once, the inward flow of positive charges carried by Na+ ions depolarizes the postsynaptic membrane sufficiently to initiate an action potential. This prokaryotic nAChR variant is known as the GLIC receptor, after the species in which it was identified, cys-loop receptors have structural elements that are well conserved, with a large extracellular domain harboring an alpha-helix and 10 beta-strands. Following the ECD, four segments are connected by intracellular and extracellular loop structures. Except the TMS 3-4 loop, their lengths are only 7-14 residues, the TMS 3-4 loop forms the largest part of the intracellular domain and exhibits the most variable region between all of these homologous receptors. The ICD is defined by the TMS 3-4 loop together with the TMS 1-2 loop preceding the ion channel pore, nevertheless, this intracellular loop appears to function in desensitization, modulation of channel physiology by pharmacological substances, and posttranslational modifications. Motifs important for trafficking are therein, and the ICD interacts with scaffold proteins enabling inhibitory synapse formation, the ionotropic glutamate receptors bind the neurotransmitter glutamate. They form tetramers with each consisting of an extracellular amino terminal domain, an extracellular ligand binding domain. The transmembrane domain of each contains three transmembrane helices as well as a half membrane helix with a reentrant loop
8.
Chemical synapse
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Chemical synapses are biological junctions through which neurons signals can be exchanged to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the nervous system. They are crucial to the computations that underlie perception and thought. They allow the system to connect to and control other systems of the body. At a chemical synapse, one neuron releases neurotransmitter molecules into a space that is adjacent to another neuron. The neurotransmitters are kept within small sacs called vesicles, and are released into the synaptic cleft by exocytosis and these molecules then bind to receptors on the postsynaptic cells side of the synaptic cleft. The adult human brain is estimated to contain from 1014 to 5 ×1014 synapses, every cubic millimeter of cerebral cortex contains roughly a billion of them. The word synapse comes from synaptein, which Sir Charles Scott Sherrington and colleagues coined from the Greek syn-, chemical synapses are not the only type of biological synapse, electrical and immunological synapses also exist. Without a qualifier, however, synapse commonly means chemical synapse, synapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are types that make far fewer. Most synapses connect axons to dendrites, but there are other types of connections, including axon-to-cell-body, axon-to-axon. Chemical synapses pass information directionally from a cell to a postsynaptic cell and are therefore asymmetric in structure. Synaptic vesicles are docked at the plasma membrane at regions called active zones. Immediately opposite is a region of the cell containing neurotransmitter receptors. Immediately behind the postsynaptic membrane is a complex of interlinked proteins called the postsynaptic density. Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors, the receptors and PSDs are often found in specialized protrusions from the main dendritic shaft called dendritic spines. Synapses may be described as symmetric or asymmetric, when examined under an electron microscope, asymmetric synapses are characterized by rounded vesicles in the presynaptic cell, and a prominent postsynaptic density. Symmetric synapses in contrast have flattened or elongated vesicles, and do not contain a prominent postsynaptic density, the synaptic cleft is a gap between the pre- and postsynaptic cells that is about 20 nm wide
9.
Resting potential
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Apart from the latter two, which occur in excitable cells, membrane voltage in the majority of non-excitable cells can also undergo changes in response to environmental or intracellular stimuli. Conventionally, resting membrane potential can be defined as a stable, ground value of transmembrane voltage in animal. Any voltage is a difference in potential between two points—for example, the separation of positive and negative electric charges on opposite sides of a resistive barrier. The typical resting membrane potential of a cell arises from the separation of ions from intracellular. Again, because of the relative permeability for potassium, the resulting membrane potential is almost always close to the potassium reversal potential. But in order for this process to occur, a gradient of potassium ions must first be set up. This work is done by the ion pumps/transporters and/or exchangers and generally is powered by ATP, in other cases, for example, a membrane potential may be established by acidification of the inside of a membranous compartment. Cell membranes are permeable to only a subset of ions. These usually include potassium ions, chloride ions, bicarbonate ions, to simplify the description of the ionic basis of the resting membrane potential, it is most useful to consider only one ionic species at first, and consider the others later. Since trans-plasma-membrane potentials are almost always determined primarily by potassium permeability, Panel 1 of the diagram shows a diagrammatic representation of a simple cell where a concentration gradient has already been established. This panel is drawn as if the membrane has no permeability to any ion, there is no membrane potential, because despite there being a concentration gradient for potassium, there is no net charge imbalance across the membrane. There would be net movement from the side of the membrane with a concentration of the ion to the side with lower concentration. Such a movement of one ion across the membrane would result in a net imbalance of charge across the membrane and this is a common mechanism by which many cells establish a membrane potential. In panel 2 of the diagram, the membrane has been made permeable to potassium ions. These anions are mostly contributed by protein, there is energy stored in the potassium ion concentration gradient that can be converted into an electrical gradient when potassium ions move out of the cell. An internal K+ is simply more likely to leave the cell than an extracellular K+ is to enter it and it is a matter of simple diffusion doing work by dissipating the concentration gradient. As potassium leaves the cell, it is leaving behind the anions, therefore, a charge separation is developing as K+ leaves the cell. This charge separation creates a transmembrane voltage and this transmembrane voltage is the membrane potential
10.
Synaptic vesicle
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In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel, Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell. The area in the axon that holds groups of vesicles is a terminal or bouton. Up to 130 vesicles can be released per bouton over a period of stimulation at 0.2 Hz. In the human brain region V1 synaptic vesicles have a diameter of 39.5 nanometers with a standard deviation of 5.1 nanometers. With the advent of modern electron microscopic techniques in the early 1950s, the term synaptic vesicle was first introduced by De Robertis and Bennett in 1954. It was thus reasonable to hypothesize that the substance was contained in such vesicles. The missing link was the demonstration that the acetylcholine is actually contained in synaptic vesicles. Two competing laboratories were involved in work, that of Victor P. Both groups released synaptic vesicles from isolated synaptosomes by osmotic shock, the content of acetylcholine in a vesicle was originally estimated to be 1000–2000 molecules. Subsequent work identified the vesicular localization of other neurotransmitters, such as acids, catecholamines, serotonin. Later, synaptic vesicles could also be isolated from tissues such as the superior cervical ganglion. The isolation of highly purified fractions of cholinergic synaptic vesicles from the ray Torpedo electric organ was an important step forward in the study of vesicle biochemistry, Synaptic vesicles are relatively simple because only a limited number of proteins fit into a sphere of 40 nm diameter. The necessary proton gradient is created by V-ATPase, which breaks down ATP for energy, vesicular transporters move neurotransmitters from the cells cytoplasm into the synaptic vesicles. Vesicular glutamate transporters, for example, sequester glutamate into vesicles by this process and they include intrinsic membrane proteins, peripherally bound proteins, and proteins such as SNAREs. Many but not all of the synaptic vesicle proteins interact with non-vesicular proteins and are linked to specific functions. The stoichiometry for the movement of different neurotransmitters into a vesicle is given in the following table, recently, it has been discovered that synaptic vesicles also contain small RNA molecules, including transfer RNA fragments, Y RNA fragments and mirRNAs. This discovery is believed to have impact on studying chemical synapses
11.
Membrane potential
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Membrane potential is the difference in electric potential between the interior and the exterior of a biological cell. With respect to the exterior of the cell, typical values of membrane potential range from –40 mV to –80 mV, all animal cells are surrounded by a membrane composed of a lipid bilayer with proteins embedded in it. The membrane serves as both an insulator and a barrier to the movement of ions. Ion pumps and ion channels are electrically equivalent to a set of batteries and resistors inserted in the membrane, and therefore create a voltage between the two sides of the membrane. Virtually all eukaryotic cells maintain a non-zero transmembrane potential, usually with a voltage in the cell interior as compared to the cell exterior ranging from –40 mV to –80 mV. The membrane potential has two basic functions, first, it allows a cell to function as a battery, providing power to operate a variety of molecular devices embedded in the membrane. Second, in electrically excitable cells such as neurons and muscle cells, signals are generated by opening or closing of ion channels at one point in the membrane, producing a local change in the membrane potential. This change in the field can be quickly affected by either adjacent or more distant ion channels in the membrane. Those ion channels can open or close as a result of the potential change. In non-excitable cells, and in cells in their baseline states. For neurons, typical values of the potential range from –70 to –80 millivolts, that is. The opening and closing of ion channels can induce a departure from the resting potential and this is called a depolarization if the interior voltage becomes less negative, or a hyperpolarization if the interior voltage becomes more negative. Action potentials are generated by the activation of certain voltage-gated ion channels, in neurons, the factors that influence the membrane potential are diverse. They include numerous types of ion channels, some of which are chemically gated, the membrane potential in a cell derives ultimately from two factors, electrical force and diffusion. Electrical force arises from the attraction between particles with opposite electrical charges and the mutual repulsion between particles with the same type of charge. Diffusion arises from the tendency of particles to redistribute from regions where they are highly concentrated to regions where the concentration is low. Voltage, which is synonymous with difference in potential, is the ability to drive an electric current across a resistance. Indeed, the simplest definition of a voltage is given by Ohms law, V=IR, where V is voltage, I is current and R is resistance
