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108-397: GABA A R are members of the ligand-gated ion channel receptor superfamily, which is a chloride channel family with a dozen or more heterotetrametric subtypes and 19 distinct subunits. These subtypes have distinct brain regional and subcellular localization, age-dependent expression, and the ability to undergo plastic alterations in response to experience, including drug exposure. GABA A R

216-593: A medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane , diethyl ether , propofol , etomidate , ketamine , pentobarbital , lorazepam and midazolam . Sedation is typically used in minor surgical procedures such as endoscopy , vasectomy , or dentistry and for reconstructive surgery, some cosmetic surgeries, removal of wisdom teeth , or for high-anxiety patients. Sedation methods in dentistry include inhalation sedation (using nitrous oxide ), oral sedation, and intravenous (IV) sedation. Inhalation sedation

324-554: A neurotransmitter . Other ion channels open and close with mechanical forces. Still other ion channels—such as those of sensory neurons —open and close in response to other stimuli, such as light, temperature or pressure. Leakage channels are the simplest type of ion channel, in that their permeability is more or less constant. The types of leakage channels that have the greatest significance in neurons are potassium and chloride channels. Even these are not perfectly constant in their properties: First, most of them are voltage-dependent in

432-472: A GABA A receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABA A receptor. Whilst this was a major development, the majority of GABA A receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site. This was finally elucidated in 2018 by the publication of a high resolution cryo-EM structure of rat α1β1γ2S receptor and human α1β2γ2 receptor bound with GABA and

540-883: A cell has also been defined as the ease with which a response may be triggered. The resting and threshold potentials forms the basis of cell excitability and these processes are fundamental for the generation of graded and action potentials. The most important regulators of cell excitability are the extracellular electrolyte concentrations (i.e. Na , K , Ca , Cl , Mg ) and associated proteins. Important proteins that regulate cell excitability are voltage-gated ion channels , ion transporters (e.g. Na+/K+-ATPase , magnesium transporters , acid–base transporters ), membrane receptors and hyperpolarization-activated cyclic-nucleotide-gated channels . For example, potassium channels and calcium-sensing receptors are important regulators of excitability in neurons , cardiac myocytes and many other excitable cells like astrocytes . Calcium ion

648-465: A child, one must consider the type of procedure planned (painful or nonpainful), the duration of the procedure (important in choosing the appropriate sedative), the underlying medical condition of the patient (proper fasting, contracted blood volume, interaction with other medications, and intact mechanisms of drug elimination), the need for anxiolysis or narcosis , and experience with alternative techniques or routes of administration. A child undergoing

756-457: A circuit. The idea of a voltage at a single point is meaningless. It is conventional in electronics to assign a voltage of zero to some arbitrarily chosen element of the circuit, and then assign voltages for other elements measured relative to that zero point. There is no significance in which element is chosen as the zero point—the function of a circuit depends only on the differences not on voltages per se . However, in most cases and by convention,

864-450: A conceptually similar way to the sodium-potassium pump, except that in each cycle it exchanges three Na from the extracellular space for one Ca from the intracellular space. Because the net flow of charge is inward, this pump runs "downhill", in effect, and therefore does not require any energy source except the membrane voltage. Its most important effect is to pump calcium outward—it also allows an inward flow of sodium, thereby counteracting

972-408: A departure from the resting potential. This is called a depolarization if the interior voltage becomes less negative (say from –70 mV to –60 mV), or a hyperpolarization if the interior voltage becomes more negative (say from –70 mV to –80 mV). In excitable cells, a sufficiently large depolarization can evoke an action potential , in which the membrane potential changes rapidly and significantly for

1080-425: A diffusion barrier to the movement of ions . Transmembrane proteins , also known as ion transporter or ion pump proteins, actively push ions across the membrane and establish concentration gradients across the membrane, and ion channels allow ions to move across the membrane down those concentration gradients. Ion pumps and ion channels are electrically equivalent to a set of batteries and resistors inserted in

1188-470: A diverse range of therapeutically significant neuropharmacological drugs. Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl will flow into the cell. This causes an inhibitory effect on neurotransmission by diminishing

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1296-426: A fixed time course. Excitable cells include neurons , muscle cells, and some secretory cells in glands . Even in other types of cells, however, the membrane voltage can undergo changes in response to environmental or intracellular stimuli. For example, depolarization of the plasma membrane appears to be an important step in programmed cell death . The interactions that generate the resting potential are modeled by

1404-415: A form of non-electrical excitability based on intracellular calcium variations related to the expression of several receptors through which they can detect the synaptic signal. In neurons, there are different membrane properties in some portions of the cell, for example, dendritic excitability endows neurons with the capacity for coincidence detection of spatially separated inputs. Electrophysiologists model

1512-424: A lesser number of sodium ions than chloride ions in solution A. This means that there is a net positive charge in solution B from the higher concentration of positively charged sodium ions than negatively charged chloride ions. Likewise, there is a net negative charge in solution A from the greater concentration of negative chloride ions than positive sodium ions. Since opposite charges attract and like charges repel,

1620-416: A major role in the action potentials of some algae , but plays a negligible role in the action potentials of most animals. Ions cross the cell membrane under two influences: diffusion and electric fields . A simple example wherein two solutions—A and B—are separated by a porous barrier illustrates that diffusion will ensure that they will eventually mix into equal solutions. This mixing occurs because of

1728-401: A medical history in assessing the applicable degree of sedation in patients in order to avoid under-sedation (the patient risks experiencing pain or distress) and over-sedation (the patient risks side effects such as suppression of breathing, which might lead to death). Examples of sedation scales include MSAT (Minnesota Sedation Assessment Tool), UMSS (University of Michigan Sedation Scale),

1836-455: A number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines , nonbenzodiazepines , neuroactive steroids , barbiturates , alcohol (ethanol), inhaled anaesthetics , kavalactones , cicutoxin , and picrotoxin , among others. Much like the GABA A receptor,

1944-589: A result, the IUPHAR has recommended that the terms " BZ receptor ", " GABA/BZ receptor " and " omega receptor " no longer be used and that the term " benzodiazepine receptor " be replaced with " benzodiazepine site ". Benzodiazepines like diazepam and midazolam act as positive allosteric modulators for GABA A receptors. When these receptors are activated, there's a rise in intracellular chloride levels, resulting in cell membrane hyperpolarization and decreased excitation. In order for GABA A receptors to be sensitive to

2052-422: A short time (on the order of 1 to 100 milliseconds), often reversing its polarity. 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 and some of which are voltage-gated. Because voltage-gated ion channels are controlled by

2160-454: A specialized voltmeter. By convention, the zero potential value is assigned to the outside of the cell and the sign of the potential difference between the outside and the inside is determined by the potential of the inside relative to the outside zero. In mathematical terms, the definition of voltage begins with the concept of an electric field E , a vector field assigning a magnitude and direction to each point in space. In many situations,

2268-432: A thorough pre-sedation evaluation and this process includes pre-sedation history and physicals with emphasis on the determining characteristics that indicate potential risks to the patient and potential difficult airway management . This process can also reveal if the sedation period needs to be prolonged or additional therapeutic procedures are required. Sedation scales are used in medical situations in conjunction with

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2376-581: A volt), but calculations show that this generates an electric field close to the maximum that the membrane can sustain—it has been calculated that a voltage difference much larger than 200 millivolts could cause dielectric breakdown , that is, arcing across the membrane. The resistance of a pure lipid bilayer to the passage of ions across it is very high, but structures embedded in the membrane can greatly enhance ion movement, either actively or passively , via mechanisms called facilitated transport and facilitated diffusion . The two types of structure that play

2484-403: A voltage change but only after a delay. One of the most important members of this group is a type of voltage-gated sodium channel that underlies action potentials—these are sometimes called Hodgkin-Huxley sodium channels because they were initially characterized by Alan Lloyd Hodgkin and Andrew Huxley in their Nobel Prize-winning studies of the physiology of the action potential. The channel

2592-675: A γ (α 2 β 2 γ). In neurons themselves, the type of GABA A receptor subunits and their densities can vary between cell bodies and dendrites . Benzodiazepines and barbiturates amplify the inhibitory effects mediated by the GABAA receptor. GABA A receptors can also be found in other tissues, including leydig cells , placenta , immune cells , liver , bone growth plates and several other endocrine tissues . Subunit expression varies between 'normal' tissue and malignancies , as GABA A receptors can influence cell proliferation . A number of ligands have been found to bind to various sites on

2700-406: Is a type of RC circuit (resistance-capacitance circuit), and its electrical properties are very simple. Starting from any initial state, the current flowing across either the conductance or the capacitance decays with an exponential time course, with a time constant of τ = RC , where C is the capacitance of the membrane patch, and R = 1/g net is the net resistance. For realistic situations,

2808-555: Is also sometimes referred to as "relative analgesia". Sedation is also used extensively in the intensive care unit so that patients who are being ventilated tolerate having an endotracheal tube in their trachea . It can also be used during a long term brain EEG to help patient relax. There are studies claiming that sedation accounts for 40 percent to 50 percent procedure-related complications. Airway obstruction , apnea , and hypotension are not uncommon during sedation and require

2916-420: Is also the molecular target of the benzodiazepine class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor site on the protein complex as does the endogenous ligand GABA (whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABA A receptors. While

3024-964: Is also the most important second messenger in excitable cell signaling . Activation of synaptic receptors initiates long-lasting changes in neuronal excitability. Thyroid , adrenal and other hormones also regulate cell excitability, for example, progesterone and estrogen modulate myometrial smooth muscle cell excitability. Many cell types are considered to have an excitable membrane. Excitable cells are neurons, muscle ( cardiac , skeletal , smooth ), vascular endothelial cells , pericytes , juxtaglomerular cells , interstitial cells of Cajal , many types of epithelial cells (e.g. beta cells , alpha cells , delta cells , enteroendocrine cells , pulmonary neuroendocrine cells , pinealocytes ), glial cells (e.g. astrocytes), mechanoreceptor cells (e.g. hair cells and Merkel cells ), chemoreceptor cells (e.g. glomus cells , taste receptors ), some plant cells and possibly immune cells . Astrocytes display

3132-502: Is approximately +66 mV with approximately 12 mM sodium inside and 140 mM outside. A neuron 's resting membrane potential actually changes during the development of an organism. In order for a neuron to eventually adopt its full adult function, its potential must be tightly regulated during development. As an organism progresses through development the resting membrane potential becomes more negative. Glial cells are also differentiating and proliferating as development progresses in

3240-418: Is closed at the resting voltage level, but opens abruptly when the voltage exceeds a certain threshold, allowing a large influx of sodium ions that produces a very rapid change in the membrane potential. Recovery from an action potential is partly dependent on a type of voltage-gated potassium channel that is closed at the resting voltage level but opens as a consequence of the large voltage change produced during

3348-498: Is disrupted in numerous neurodevelopmental diseases, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and that it is a crucial potential target for therapeutic intervention. GABA A receptors are members of the large pentameric ligand gated ion channel (previously referred to as " Cys -loop" receptors) super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors , glycine receptors , and

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3456-411: Is either open or closed. In general, closed states correspond either to a contraction of the pore—making it impassable to the ion—or to a separate part of the protein, stoppering the pore. For example, the voltage-dependent sodium channel undergoes inactivation , in which a portion of the protein swings into the pore, sealing it. This inactivation shuts off the sodium current and plays a critical role in

3564-404: Is established when the membrane has permeability to one or more ions. In the simplest case, illustrated in the top diagram ("Ion concentration gradients"), if the membrane is selectively permeable to potassium, these positively charged ions can diffuse down the concentration gradient to the outside of the cell, leaving behind uncompensated negative charges. This separation of charges is what causes

3672-402: Is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout . Membrane potential Membrane potential (also transmembrane potential or membrane voltage ) is the difference in electric potential between

3780-545: Is important because it gives the voltage that acts on channels permeable to that ion—in other words, it gives the voltage that the ion concentration gradient generates when it acts as a battery . The equilibrium potential of a particular ion is usually designated by the notation E ion .The equilibrium potential for any ion can be calculated using the Nernst equation . For example, reversal potential for potassium ions will be as follows: where Even if two different ions have

3888-407: Is intravenous sedation using Midazolam . This requires a needle to be put into a vein to deliver the medication; this is known as an IV cannula. Indications: Contraindications: Present drugs commonly used to sedate children: Methohexital ; Thiopental ; Benzodiazepines ; Diazepam ; Midazolam ; Ketamine ; Opioids ; Morphine ; Meperidine ; Fentanyl . Whenever it is necessary to sedate

3996-742: Is not just the target of agonist depressants and antagonist convulsants, but most GABA A R medicines also act at additional (allosteric) binding sites on GABA A R proteins. Some sedatives and anxiolytics, such as benzodiazepines and related medicines, act on GABA A R subtype-dependent extracellular domain sites. Alcohols and neurosteroids, among other general anesthetics, act at GABA A R subunit-interface transmembrane locations. High anesthetic dosages of ethanol act on GABA A R subtype-dependent transmembrane domain locations. Ethanol acts at GABA A R subtype-dependent extracellular domain locations at low intoxication concentrations. Thus, GABA A R subtypes have pharmacologically distinct receptor binding sites for

4104-406: Is presumed to be due to the higher activity of chloride transporters, such as NKCC1 , transporting chloride into cells which are present early in development, whereas, for instance, KCC2 transports chloride out of cells and is the dominant factor in establishing the chloride gradient later in development. These depolarization events have shown to be key in neuronal development. In the mature neuron,

4212-420: Is referred to as a resting potential or resting voltage. This term is used for the membrane potential of non-excitable cells, but also for the membrane potential of excitable cells in the absence of excitation. In excitable cells, the other possible states are graded membrane potentials (of variable amplitude), and action potentials, which are large, all-or-nothing rises in membrane potential that usually follow

4320-426: Is required to move a positive charge from the interior to the exterior. However, thermal kinetic energy allows ions to overcome the potential difference. For a selectively permeable membrane, this permits a net flow against the gradient. This is a kind of osmosis . 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

4428-540: Is the endogenous compound that causes this receptor to open; once bound to GABA, the protein receptor changes conformation within the membrane, opening the pore in order to allow chloride anions ( Cl ) and, to a lesser extent, bicarbonate ions ( HCO 3 ) to pass down their electrochemical gradient . The binding site to GABA is about 80Å away from the narrowest part of the ion channel. Recent computational studies have suggested an allosteric mechanism whereby GABA binding leads to ion channel opening. Because

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4536-489: Is the ability to drive an electric current across a resistance. Indeed, the simplest definition of a voltage is given by Ohm's law : V=IR, where V is voltage, I is current and R is resistance. If a voltage source such as a battery is placed in an electrical circuit, the higher the voltage of the source the greater the amount of current that it will drive across the available resistance. The functional significance of voltage lies only in potential differences between two points in

4644-408: Is used for transmitting signals between different parts of a cell. Signals are generated in excitable cells 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 electric field can be quickly sensed by either adjacent or more distant ion channels in the membrane. Those ion channels can then open or close as a result of

4752-533: The 5HT 3 receptor . There are numerous subunit isoforms for the GABA A receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties. In humans, the units are as follows: There are three ρ units ( GABRR1 , GABRR2 , GABRR3 ); however, these do not coassemble with the classical GABA A units listed above, but rather homooligomerize to form GABA A -ρ receptors (formerly classified as GABA C receptors but now this nomenclature has been deprecated). Given

4860-585: The Goldman equation . This is similar in form to the Nernst equation shown above, in that it is based on the charges of the ions in question, as well as the difference between their inside and outside concentrations. However, it also takes into consideration the relative permeability of the plasma membrane to each ion in question. Sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate

4968-421: The brain . The addition of these glial cells increases the organism's ability to regulate extracellular potassium . The drop in extracellular potassium can lead to a decrease in membrane potential of 35 mV. Cell excitability is the change in membrane potential that is necessary for cellular responses in various tissues. Cell excitability is a property that is induced during early embriogenesis. Excitability of

5076-406: The reversal potential for chloride in most mature neurons is close to or more negative than the resting membrane potential , activation of GABA A receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential . The net effect therefore typically inhibitory, reducing

5184-485: The z-drugs may also be hallucinogenic . Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion . Some of the subtype-selective negative allosteric modulators such as α 5 IA are being investigated for their nootropic effects, as well as treatments for the unwanted side effects of other GABAergic drugs. Advances in molecular pharmacology and genetic manipulation of rat genes have revealed that distinct subtypes of

5292-465: The GABA A channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP). The endogenous ligand that binds to the benzodiazepine site is inosine . Proper developmental, neuronal cell-type-specific, and activity-dependent GABAergic transmission control is required for nearly all aspects of CNS function. It has been proposed that the GABAergic system

5400-421: The GABA A receptor complex and modulate it besides GABA itself. A ligand can possess one or more properties of the following types. Unfortunately the literature often does not distinguish these types properly. Ligands which contribute to receptor activation typically have anxiolytic , anticonvulsant , amnesic , sedative , hypnotic , euphoriant , and muscle relaxant properties. Some such as muscimol and

5508-747: The GABA A receptor mediate certain parts of the anaesthetic behavioral repertoire. A useful property of the many benzodiazepine site allosteric modulators is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABA A receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABA A receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects. Few subtype selective ligands have gone into clinical use as yet, with

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5616-418: The GABA A subtypes, but current research in this area is focused mainly on producing α 2 -selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia. The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABA A receptor, and also produces different effects on binding, with the benzodiazepines increasing

5724-410: The GABA B receptor is an obligatory heterodimer consisting of GABA B1 and GABA B2 subunits. These subunits include an extracellular Venus Flytrap domain (VFT) and a transmembrane domain containing seven α-helices (7TM domain). These structural components play a vital role in intricately modulating neurotransmission and interactions with drugs. The ionotropic GABA A receptor protein complex

5832-450: The GABA receptors at the synapse, this is known as phasic inhibition. However, the GABA escaping from the synaptic cleft can activate receptors on presynaptic terminals or at neighbouring synapses on the same or adjacent neurons (a phenomenon termed 'spillover') in addition to the constant, low GABA concentrations in the extracellular space results in persistent activation of the GABA A receptors known as tonic inhibition. The ligand GABA

5940-854: The Ramsay Scale (Ramsay, et al. 1974) and the RASS ( Richmond Agitation-Sedation Scale ). The American Society of Anesthesiologists defines the continuum of sedation as follows: In the United Kingdom, deep sedation is considered to be a part of the spectrum of general anesthesia , as opposed to conscious sedation. In addition to the aforementioned precautions, patients should be interviewed to determine if they have any other condition that may lead to complications while undergoing treatment. Any head, neck, or spinal cord injuries should be noted as well as any diagnosis of osteoporosis . The most common standard conscious sedation technique for adults

6048-403: The action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABA A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA A receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates

6156-434: The action potential is the sodium–potassium pump , which transports three sodium ions out of the cell and two potassium ions in. As a consequence, the concentration of potassium ions K inside the neuron is roughly 30-fold larger than the outside concentration, whereas the sodium concentration outside is roughly five-fold larger than inside. In a similar manner, other ions have different concentrations inside and outside

6264-409: The action potential. Ion channels can be classified by how they respond to their environment. For example, the ion channels involved in the action potential are voltage-sensitive channels ; they open and close in response to the voltage across the membrane. Ligand-gated channels form another important class; these ion channels open and close in response to the binding of a ligand molecule , such as

6372-433: The action potential. The reversal potential (or equilibrium potential ) of an ion is the value of transmembrane voltage at which diffusive and electrical forces counterbalance, so that there is no net ion flow across the membrane. This means that the transmembrane voltage exactly opposes the force of diffusion of the ion, such that the net current of the ion across the membrane is zero and unchanging. The reversal potential

6480-425: The activity of the neuron, although depolarizing currents have been observed in response to GABA in immature neurons in early development. This effect during development is due to a modified Cl gradient wherein the anions leave the cells through the GABA A receptors, since their intracellular chlorine concentration is higher than the extracellular. The difference in extracellular chlorine anion concentration

6588-403: The capacitance of the membrane is more or less fixed, but the resistance is highly variable. The thickness of a plasma membrane is estimated to be about 7-8 nanometers. Because the membrane is so thin, it does not take a very large transmembrane voltage to create a strong electric field within it. Typical membrane potentials in animal cells are on the order of 100 millivolts (that is, one tenth of

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6696-490: The chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABA A -mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABA B IPSP (−100 mV). The active site of the GABA A receptor is the binding site for GABA and several drugs such as muscimol , gaboxadol , and bicuculline . The protein also contains

6804-401: The channel, i.e. single-channel current amplitude, is determined by the maximum channel conductance and electrochemical driving force for that ion, which is the difference between the instantaneous value of the membrane potential and the value of the reversal potential . A channel may have several different states (corresponding to different conformations of the protein), but each such state

6912-506: The chemical ligand that gates them is released by the presynaptic axon terminal . One example of this type is the AMPA receptor , a receptor for the neurotransmitter glutamate that when activated allows passage of sodium and potassium ions. Another example is the GABA A receptor , a receptor for the neurotransmitter GABA that when activated allows passage of chloride ions. Neurotransmitter receptors are activated by ligands that appear in

7020-464: The difference in their concentrations. The region with high concentration will diffuse out toward the region with low concentration. To extend the example, let solution A have 30 sodium ions and 30 chloride ions. Also, let solution B have only 20 sodium ions and 20 chloride ions. Assuming the barrier allows both types of ions to travel through it, then a steady state will be reached whereby both solutions have 25 sodium ions and 25 chloride ions. If, however,

7128-409: The effects of ionic concentration differences, ion channels, and membrane capacitance in terms of an equivalent circuit , which is intended to represent the electrical properties of a small patch of membrane. The equivalent circuit consists of a capacitor in parallel with four pathways each consisting of a battery in series with a variable conductance. The capacitance is determined by the properties of

7236-541: The electric field is a conservative field , which means that it can be expressed as the gradient of a scalar function V , that is, E = –∇ V . This scalar field V is referred to as the voltage distribution. The definition allows for an arbitrary constant of integration—this is why absolute values of voltage are not meaningful. In general, electric fields can be treated as conservative only if magnetic fields do not significantly influence them, but this condition usually applies well to biological tissue. Because

7344-420: The electric field is the gradient of the voltage distribution, rapid changes in voltage within a small region imply a strong electric field; on the converse, if the voltage remains approximately the same over a large region, the electric fields in that region must be weak. A strong electric field, equivalent to a strong voltage gradient, implies that a strong force is exerted on any charged particles that lie within

7452-551: The exception of zolpidem which is reasonably selective for α 1 , but several more selective compounds are in development such as the α 3 -selective drug adipiplon . There are many examples of subtype-selective compounds which are widely used in scientific research, including: Diazepam is a benzodiazepine medication that is FDA approved for the treatment of anxiety disorders, the short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief,

7560-496: The extracellular area, but there are other types of ligand-gated channels that are controlled by interactions on the intracellular side. Voltage-gated ion channels , also known as voltage dependent ion channels , are channels whose permeability is influenced by the membrane potential. They form another very large group, with each member having a particular ion selectivity and a particular voltage dependence. Many are also time-dependent—in other words, they do not respond immediately to

7668-450: The five subunits of the receptor (see images above) can be altered in such a way that for example the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one. There are estimates that about 2–3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It

7776-454: The frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound. Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled. Also note that some GABA A agonists such as muscimol and gaboxadol do bind to

7884-653: The inhibitory effect of the available GABA leading to sedative and anxiolytic effects. Different benzodiazepines have different affinities for GABA A receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation , ataxia and amnesia , whereas those with higher activity at GABA A receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity. Anticonvulsant effects can be produced by agonists acting at any of

7992-629: The interior and the exterior of a biological cell . It equals the interior potential minus the exterior potential. This is the energy (i.e. work ) per charge which is required to move a (very small) positive charge at constant velocity across the cell membrane from the exterior to the interior. (If the charge is allowed to change velocity, the change of kinetic energy and production of radiation must be taken into account.) Typical values of membrane potential, normally given in units of milli volts and denoted as mV, range from –80 mV to –40 mV. For such typical negative membrane potentials, positive work

8100-424: The ion channels that are potentially permeable to that ion, including leakage channels, ligand-gated channels, and voltage-gated ion channels. For fixed ion concentrations and fixed values of ion channel conductance, the equivalent circuit can be further reduced, using the Goldman equation as described below, to a circuit containing a capacitance in parallel with a battery and conductance. In electrical terms, this

8208-444: The ion pumps are turned off by removing their energy source, or by adding an inhibitor such as ouabain , the axon can still fire hundreds of thousands of action potentials before their amplitudes begin to decay significantly. In particular, ion pumps play no significant role in the repolarization of the membrane after an action potential. Another functionally important ion pump is the sodium-calcium exchanger . This pump operates in

8316-401: The ions are now also influenced by electrical fields as well as forces of diffusion. Therefore, positive sodium ions will be less likely to travel to the now-more-positive B solution and remain in the now-more-negative A solution. The point at which the forces of the electric fields completely counteract the force due to diffusion is called the equilibrium potential. At this point, the net flow of

8424-490: The large number of GABA A receptors, a great diversity of final pentameric receptor subtypes is possible. Methods to produce cell-based laboratory access to a greater number of possible GABA A receptor subunit combinations allow teasing apart of the contribution of specific receptor subtypes and their physiological and pathophysiological function and role in the CNS and in disease. GABA A receptors are responsible for most of

8532-515: The largest roles are ion channels and ion pumps , both usually formed from assemblages of protein molecules. Ion channels provide passageways through which ions can move. In most cases, an ion channel is permeable only to specific types of ions (for example, sodium and potassium but not chloride or calcium), and sometimes the permeability varies depending on the direction of ion movement. Ion pumps, also known as ion transporters or carrier proteins, actively transport specific types of ions from one side of

8640-466: The lipid bilayer, and is taken to be fixed. Each of the four parallel pathways comes from one of the principal ions, sodium, potassium, chloride, and calcium. The voltage of each ionic pathway is determined by the concentrations of the ion on each side of the membrane; see the Reversal potential section above. The conductance of each ionic pathway at any point in time is determined by the states of all

8748-457: The majority of GABA A receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABA A receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines, but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABA A receptors. As

8856-409: The management of certain refractory epileptic patients, and as an adjunct in severe recurrent convulsive seizures and status epilepticus. There are multiple indications that paradoxical reactions upon — for example — benzodiazepines, barbiturates, inhalational anesthetics , propofol , neurosteroids , and alcohol are associated with structural deviations of GABA A receptors. The combination of

8964-430: The membrane potential, while the membrane potential itself is influenced by these same ion channels, feedback loops that allow for complex temporal dynamics arise, including oscillations and regenerative events such as action potentials. Differences in the concentrations of ions on opposite sides of a cellular membrane lead to a voltage called the membrane potential . Many ions have a concentration gradient across

9072-414: The membrane potential. The system as a whole is electro-neutral. The uncompensated positive charges outside the cell, and the uncompensated negative charges inside the cell, physically line up on the membrane surface and attract each other across the lipid bilayer . Thus, the membrane potential is physically located only in the immediate vicinity of the membrane. It is the separation of these charges across

9180-482: The membrane that is the basis of the membrane voltage. The top diagram is only an approximation of the ionic contributions to the membrane potential. Other ions including sodium, chloride, calcium, and others play a more minor role, even though they have strong concentration gradients, because they have more limited permeability than potassium. The membrane potential in a cell derives ultimately from two factors: electrical force and diffusion. Electrical force arises from

9288-476: The membrane to the other or of providing channels through which they can move. In electrical terminology, the plasma membrane functions as a combined resistor and capacitor . Resistance arises from the fact that the membrane impedes the movement of charges across it. Capacitance arises from the fact that the lipid bilayer is so thin that an accumulation of charged particles on one side gives rise to an electrical force that pulls oppositely charged particles toward

9396-464: The membrane to the other, sometimes using energy derived from metabolic processes to do so. Ion pumps are integral membrane proteins that carry out active transport , i.e., use cellular energy (ATP) to "pump" the ions against their concentration gradient. Such ion pumps take in ions from one side of the membrane (decreasing its concentration there) and release them on the other side (increasing its concentration there). The ion pump most relevant to

9504-479: The membrane, and therefore create a voltage between the two sides of the membrane. All plasma membranes have an electrical potential across them, with the inside usually negative with respect to the outside. 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 , it

9612-407: The membrane, including potassium (K ), which is at a high concentration inside and a low concentration outside the membrane. Sodium (Na ) and chloride (Cl ) ions are at high concentrations in the extracellular region, and low concentrations in the intracellular regions. These concentration gradients provide the potential energy to drive the formation of the membrane potential. This voltage

9720-443: The mutual attraction between particles with opposite electrical charges (positive and negative) and the mutual repulsion between particles with the same type of charge (both positive or both negative). Diffusion arises from the statistical 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 electrical potential ,

9828-406: The neuron, such as calcium , chloride and magnesium . If the numbers of each type of ion were equal, the sodium–potassium pump would be electrically neutral, but, because of the three-for-two exchange, it gives a net movement of one positive charge from intracellular to extracellular for each cycle, thereby contributing to a positive voltage difference. The pump has three effects: (1) it makes

9936-548: The neutral benzodiazepine flumazenil. GABA A receptors are pentameric transmembrane receptors which consist of five subunits arranged around a central pore . Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the membrane of its neuron , usually localized at a synapse , postsynaptically. However, some isoforms may be found extrasynaptically. When vesicles of GABA are released presynaptically and activate

10044-459: The other side. The capacitance of the membrane is relatively unaffected by the molecules that are embedded in it, so it has a more or less invariant value estimated at 2 μF/cm (the total capacitance of a patch of membrane is proportional to its area). The conductance of a pure lipid bilayer is so low, on the other hand, that in biological situations it is always dominated by the conductance of alternative pathways provided by embedded molecules. Thus,

10152-405: The physiological activities of GABA in the central nervous system, and the receptor subtypes vary significantly. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. The minimal requirement to produce a GABA-gated ion channel is the inclusion of an α and a β subunit. The most common GABA A receptor is a pentamer comprising two α's, two β's, and

10260-468: The porous barrier is selective to which ions are let through, then diffusion alone will not determine the resulting solution. Returning to the previous example, let's now construct a barrier that is permeable only to sodium ions. Now, only sodium is allowed to diffuse cross the barrier from its higher concentration in solution A to the lower concentration in solution B. This will result in a greater accumulation of sodium ions than chloride ions in solution B and

10368-449: The potential change, reproducing the signal. In non-excitable cells, and in excitable cells in their baseline states, the membrane potential is held at a relatively stable value, called the resting potential . For neurons, resting potential is defined as ranging from –80 to –70 millivolts; that is, the interior of a cell has a negative baseline voltage of a bit less than one-tenth of a volt. The opening and closing of ion channels can induce

10476-430: The presence of health professionals who are suitably trained to detect and manage these problems. Aside from the respiratory depression , risks also include unintended levels of sedation, postoperative somnolence , aspiration, and adverse reactions to sedation medications. Complications could also include perforation, bleeding, and the stimulation of vasovagal reflexes . To avoid sedation risks, care providers conduct

10584-421: The pump to establish equilibrium. The pump operates constantly, but becomes progressively less efficient as the concentrations of sodium and potassium available for pumping are reduced. Ion pumps influence the action potential only by establishing the relative ratio of intracellular and extracellular ion concentrations. The action potential involves mainly the opening and closing of ion channels not ion pumps. If

10692-423: The region. Electrical signals within biological organisms are, in general, driven by ions . The most important cations for the action potential are sodium (Na ) and potassium (K ). Both of these are monovalent cations that carry a single positive charge. Action potentials can also involve calcium (Ca ), which is a divalent cation that carries a double positive charge. The chloride anion (Cl ) plays

10800-418: The same charge (i.e., K and Na ), they can still have very different equilibrium potentials, provided their outside and/or inside concentrations differ. Take, for example, the equilibrium potentials of potassium and sodium in neurons. The potassium equilibrium potential E K is −84 mV with 5 mM potassium outside and 140 mM inside. On the other hand, the sodium equilibrium potential, E Na ,

10908-448: The same charge and differ only slightly in their radius. The channel pore is typically so small that ions must pass through it in single-file order. Channel pores can be either open or closed for ion passage, although a number of channels demonstrate various sub-conductance levels. When a channel is open, ions permeate through the channel pore down the transmembrane concentration gradient for that particular ion. Rate of ionic flow through

11016-478: The same site on the GABA A receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines. Structural understanding of the GABA A receptor was initially based on homology models, obtained using crystal structures of homologous proteins like Acetylcholine binding protein (AChBP) and nicotinic acetylcholine (nACh) receptors as templates. The much sought structure of

11124-552: The sense that they conduct better in one direction than the other (in other words, they are rectifiers ); second, some of them are capable of being shut off by chemical ligands even though they do not require ligands in order to operate. Ligand-gated ion channels are channels whose permeability is greatly increased when some type of chemical ligand binds to the protein structure. Animal cells contain hundreds, if not thousands, of types of these. A large subset function as neurotransmitter receptors —they occur at postsynaptic sites, and

11232-472: The sodium concentration high in the extracellular space and low in the intracellular space; (2) it makes the potassium concentration high in the intracellular space and low in the extracellular space; (3) it gives the intracellular space a negative voltage with respect to the extracellular space. The sodium-potassium pump is relatively slow in operation. If a cell were initialized with equal concentrations of sodium and potassium everywhere, it would take hours for

11340-637: The sodium-potassium pump, but, because overall sodium and potassium concentrations are much higher than calcium concentrations, this effect is relatively unimportant. The net result of the sodium-calcium exchanger is that in the resting state, intracellular calcium concentrations become very low. Ion channels are integral membrane proteins with a pore through which ions can travel between extracellular space and cell interior. Most channels are specific (selective) for one ion; for example, most potassium channels are characterized by 1000:1 selectivity ratio for potassium over sodium, though potassium and sodium ions have

11448-476: The specific ion (in this case sodium) is zero. Every cell is enclosed in a plasma membrane , which has the structure of a lipid bilayer with many types of large molecules embedded in it. Because it is made of lipid molecules, the plasma membrane intrinsically has a high electrical resistivity, in other words a low intrinsic permeability to ions. However, some of the molecules embedded in the membrane are capable either of actively transporting ions from one side of

11556-476: The time constant usually lies in the 1—100 millisecond range. In most cases, changes in the conductance of ion channels occur on a faster time scale, so an RC circuit is not a good approximation; however, the differential equation used to model a membrane patch is commonly a modified version of the RC circuit equation. When the membrane potential of a cell goes for a long period of time without changing significantly, it

11664-407: The zero level is most often assigned to the portion of a circuit that is in contact with ground. The same principle applies to voltage in cell biology. In electrically active tissue, the potential difference between any two points can be measured by inserting an electrode at each point, for example one inside and one outside the cell, and connecting both electrodes to the leads of what is in essence

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