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Synaptic transmission

Ion pumps and ion channels maintain the resting potential of a neuron.

• All cells have a voltage (difference in electrical charge) across their plasma membrane; this voltage is called the membrane potential.

• In neurons, inputs from other neurons or specific stimuli cause changes in this membrane potential, which act as signals to transmit and process information.

• The membrane potential of a neuron that is not transmitting signals is called the resting potential and is typically between −60 and −80 mV.

• In all neurons, the resting potential depends on the ionic gradients that exist across the plasma membrane.

• In mammalian neurons, the extracellular fluid has a Na⁺ concentration of 150 millimolar (mM) and a K⁺ concentration of 5 mM.

• In the cytosol, the Na⁺ concentration is 15 mM and the K⁺ concentration is 150 mM.

• The gradients are maintained by sodium-potassium pumps in the plasma membrane.

• These ion pumps use the energy of ATP hydrolysis to actively transport Na⁺ out of the cell and K⁺ into the cell.

• Gradients of K⁺ and Na⁺ across the plasma membrane represent potential energy.

• Converting this chemical potential to electrical potential involves ion channels, pores formed by clusters of specialized proteins that span the membrane.

• Ion channels allow ions to diffuse back and forth across the membrane.

• As ions diffuse through channels, they carry with them units of electrical charge.

• Any resulting net movement of positive or negative charge generates a voltage or potential across the membrane.

• The ion channels that establish the membrane potential have selective permeability, meaning that they allow only certain ions to pass.

• For example, a potassium channel allows K⁺ to diffuse freely across the membrane but not other ions, such as Na⁺.

• A resting neuron has many open potassium channels but very few open sodium channels.

• The diffusion of K⁺ through open potassium channels is critical for the formation of the resting potential.

• In the resting mammalian neuron, ion channels allow K⁺ to pass in either direction across the membrane.

• Because the concentration of K⁺ is much higher inside the cell, there is a net outflow of potassium ions.

• Because the potassium channels allow only K⁺ to pass, Cl^- and other anions inside the cell cannot accompany the K⁺ across the membrane.

• As a result, the outflow of K⁺ leads to an excess of negative charge inside the cell.

• This buildup of negative charge within the neuron is the source of the membrane potential.

• The electrical potential itself prevents the buildup of negative charge from increasing indefinitely.

• The excess negative charges inside the cell exert an attractive force that opposes the flow of additional positively charged K⁺ ions out of the cell.

• The separation of charge (voltage) results in an electrical gradient.

• The net flow of K⁺ out of a neuron proceeds until the chemical and electrical forces are in balance.

• Consider two chambers separated by an artificial membrane containing many open ion channels, all of which allow only K⁺ to diffuse across.

• We place a solution of 140 mM potassium chloride (KCl) in the inner chamber and 5 mM KCl in the outer chamber.

• The K⁺ ions will diffuse down their concentration gradient into the outer chamber.

• Because the chloride ions (Cl^-) cannot cross the membrane, there will be an excess of negative charge in the inner chamber.

• At equilibrium, the electrical gradient will exactly balance the chemical gradient, with no further net diffusion of ions across the membrane.

• The magnitude of the membrane voltage at equilibrium for a particular ion is called that ion’s equilibrium potential (E_ion).

• For a membrane permeable to a single type of ion, E_ion can be calculated using a formula called the Nernst equation.

• At human body temperature (37°C) and for an ion with a net charge of +1, such as K⁺ or Na⁺, the Nernst equation is:

E_ion = 62 mV(log [ion]_outside/[ion]_inside)

• In our model, the membrane is permeable only to K⁺, and the Nernst equation can be used to calculate E_K, the equilibrium potential for K⁺, as -90mV.

• The minus sign indicates that K⁺ is at equilibrium when the inside of the membrane is 90 mV more negative than the outside.

• Now assume that the membrane is permeable only to Na⁺; then E_Na, the equilibrium potential for Na⁺, is +62 mV.

• This value indicates that, with this Na⁺ concentration gradient, Na⁺ is at equilibrium when the inside of the membrane is 62 mV more positive than the outside.

• Although the equilibrium potential for K⁺ is -90 mV, the resting potential of a mammalian neuron is somewhat less negative because of the small but steady movement of Na⁺ across the few open sodium channels in a resting neuron.

• If the only open channels were selective for Na⁺, then a tenfold higher concentration of sodium in the outer chamber would result in an equilibrium potential (E_Na) of +62 mV.

• Instead, the resting potential of an actual neuron is -60 to -80 mV.

• The resting potential is much closer to E_K than to E_Na in a neuron because there are many open potassium channels but only a small number of open sodium channels.

• Neither K⁺ nor Na ⁺ is at equilibrium, and there is a net flow of each ion (a current) across the membrane at rest.

• The resting potential remains steady; the K⁺ and Na⁺ currents are equal and opposite.

• Ion concentrations on either side of the membrane also remain steady because the charge separation needed to generate the resting potential is extremely small (about 10^-12 mol/cm² of membrane).

• This represents the movement of far fewer ions than would be required to alter the chemical concentration gradient.

• Under conditions that allow Na⁺ to cross the membrane more readily, the membrane potential will move toward E_Na and away from E_K.

• This is precisely what happens during the transmission of a nerve impulse along an axon.

Action potentials are the signals conducted by axons.

• The plasma membrane of a resting neuron contains many open K⁺ channels but only a few open Na⁺ channels.

• When neurons are active, the number of open channels for these ions changes.

• The change occurs because neurons have gated ion channels, which open or close in response to stimuli.

Gated ion channels are responsible for generating the signals of the nervous system.

• If a cell has gated ion channels, the membrane’s permeability to certain ions and its membrane potential may change in response to stimuli that open or close the ion channels.

• The resulting changes in membrane potential can be measured directly by intracellular recordings of the state of a single neuron in real time.

• Consider what happens when the gated K⁺ channels that are closed in a resting neuron open.

• Opening more K⁺ channels increases the membrane’s permeability to K⁺, increasing the net diffusion of K⁺ out of the neuron.

• The inside of the membrane becomes more negative.

• As the membrane potential approaches E_K (^-90 mV at 37°C), the separation of charge, or polarity, increases.

• This increase in the magnitude of the membrane potential is a hyperpolarization.

• Hyperpolarization results from any stimulus that increases either the outflow of positive ions or the inflow of negative ions.

• Although opening K⁺ channels causes hyperpolarization, opening some other types of ion channels, such as gated sodium channels, makes the inside of the membrane less negative.

• This reduction in the magnitude of the membrane potential is called a depolarization.

• Gated Na⁺ channels open, Na⁺ diffuses into the cell, and the inside of the membrane becomes less negative.

• These changes in membrane potential are called graded potentials because the magnitude of the change—either hyperpolarization or depolarization—varies with the strength of the stimulus.

• A larger stimulus causes a larger change in membrane permeability and, thus, a larger change in membrane potential.

• Graded potentials are not the actual nerve signals that travel along axons, but they have a major effect on the generation of nerve signals.

Neurons communicate with other cells at synapses.

• When an action potential reaches the terminal of the axon, it generally stops.

• However, information is transmitted from a neuron to another cell at the synapse.

• Some synapses, called electrical synapses, contain gap junctions that do allow electrical current to flow directly from cell to cell.

• Action potentials travel directly from the presynaptic to the postsynaptic cell.

• In both vertebrates and invertebrates, electrical synapses synchronize the activity of neurons responsible for rapid, invariant behaviors.

• For example, electrical synapses associated with the giant axons of squids and lobsters facilitate the swift execution of escape responses. There are also many electrical synapses in the vertebrate brain.

• The vast majority of synapses are chemical synapses, which involve the release of a chemical neurotransmitter by the presynaptic neuron.

• The cell body and dendrites of a single postsynaptic neuron may receive inputs from chemical synapses with hundreds or thousands of synaptic terminals.

• The presynaptic neuron synthesizes the neurotransmitter and packages it in membrane-bound synaptic vesicles, which are stored in the neuron’s synaptic terminals.

• When an action potential reaches a synaptic terminal, it depolarizes the terminal membrane, opening voltage-gated calcium channels in the membrane.

• Calcium ions (Ca²⁺) then diffuse into the terminal, and the rise in Ca²⁺ concentration in the terminal causes some of the synaptic vesicles to fuse with the terminal membrane, releasing the neurotransmitter.

• The neurotransmitter diffuses across the narrow gap, called the synaptic cleft, that separates the presynaptic neuron from the postsynaptic cell.

• The effect of the neurotransmitter on the postsynaptic cell may be direct or indirect.

• Information transfer at the synapse can be modified more readily at chemical synapses than at electrical synapses.

• A variety of factors can affect the amount of neurotransmitter that is released or the responsiveness of the postsynaptic cell.

• Such modifications underlie an animal’s ability to alter its behavior and form the basis for learning or memory.

Neural integration occurs at the cellular level.

• At many chemical synapses, ligand-gated ion channels capable of binding to the neurotransmitter are clustered in the membrane of the postsynaptic cell, directly opposite the synaptic terminal.

• Binding of the neurotransmitter opens the channel and allows specific ions to diffuse across the postsynaptic membrane.

• The result is generally a postsynaptic potential, a change in the membrane potential of the postsynaptic cell.

• At some synapses, the neurotransmitter binds to a type of channel through which both Na⁺ and K⁺ can diffuse.

• When the channel opens, the postsynaptic membrane depolarizes as the membrane potential approaches a value roughly midway between E_K and E_Na.

• Because these depolarizations bring the membrane potential toward threshold, they are called excitatory postsynaptic potentials (EPSPs).

• At other synapses, a different neurotransmitter binds to channels that are selectively permeable to only K⁺ or Cl^-.

• When the channel opens, the postsynaptic membrane hyperpolarizes to produce an inhibitory postsynaptic potential (IPSP) that moves the membrane potential farther from threshold.

• The binding of neurotransmitter to postsynaptic receptors opens gated channels that allow K⁺ to diffuse out of the cell and/or Cl⁻ to diffuse into the cell.

• Various mechanisms rapidly clear neurotransmitters from the synaptic cleft, ending their effect on postsynaptic cells.

• Some neurotransmitters simply diffuse out of the synaptic cleft.

• Other neurotransmitters are removed from the synaptic cleft by an enzyme that catalyzes hydrolysis of the neurotransmitter.

• Neurotransmitters may be taken up by the presynaptic neuron through active transport and repackaged into synaptic vesicles.

• Glia actively take up neurotransmitters at some synapses and metabolize them as fuel.

• Unlike action potentials, which are all-or-none events, postsynaptic potentials are graded.

• Their magnitude varies with a number of factors, including the amount of neurotransmitter released by the presynaptic neuron.

• Postsynaptic potentials do not regenerate but rather diminish with distance from the synapse.

• Most synapses on a neuron are located on its dendrites or cell body, whereas action potentials are generally initiated at the axon hillock.

• Therefore, a single EPSP is usually too small to trigger an action potential in a postsynaptic neuron.

• Graded potentials (EPSPs and IPSPs) are summed to either depolarize or hyperpolarize a postsynaptic neuron.

• Two EPSPs produced in rapid succession at the same synapse can be added in an effect called temporal summation.

• Two EPSPs produced nearly simultaneously by different synapses on the same postsynaptic neuron can be added in an effect called spatial summation.

• Summation also applies to IPSPs: Two or more IPSPs occurring nearly simultaneously or in rapid succession have a larger hyperpolarizing effect than a single IPSP.

• Through summation, an IPSP can also counter the effect of an EPSP.

• This interplay between multiple excitatory and inhibitory inputs is the essence of integration in the nervous system.

• The axon hillock is the neuron’s integrating center, where the membrane potential at any instant represents the summed effect of all EPSPs and IPSPs.

• Whenever the membrane potential at the axon hillock reaches the threshold, an action potential is generated and travels along the axon to its synaptic terminals.

• After the refractory period, the neuron may produce another action potential, provided the membrane potential at the axon hillock once again reaches threshold.

• At some synapses, a neurotransmitter binds to a receptor that is not part of an ion channel.

• This binding activates a signal transduction pathway involving a second messenger in the postsynaptic cell.

• This form of transmission has a slower onset, but its effects have a longer duration, over minutes or even hours.

• Second messengers modulate the responsiveness of postsynaptic neurons to inputs in diverse ways, such as by altering the number of open potassium channels.

• cAMP is one of the best-studied secondary messengers in indirect synaptic transmission.

• When the neurotransmitter norepinephrine binds to its receptor, the neurotransmitter-receptor complex activates a G protein, which in turn activates adenylyl cyclase, the enzyme that converts ATP to cAMP.

• Cyclic AMP activates protein kinase A, which phosphorylates specific channel proteins in the postsynaptic membrane, causing them to open or close.

• Because of the amplifying effect of the signal transduction pathway, the binding of a neurotransmitter to a single receptor can open or close many channels.

The same neurotransmitter can produce different effects on different types of cells.

• There are more than 100 known neurotransmitters.

• Nearly all these neurotransmitters fall into a small number of groups based on chemical structure.

• The major classes of neurotransmitters are acetylcholine, biogenic amines, amino acids, neuropeptides, and gases.

• A single neurotransmitter may have more than a dozen receptors.

• The receptors for a specific neurotransmitter can vary significantly in their effects on postsynaptic cells.

• For this reason, many drugs used to treat nervous system diseases or affect brain function are targeted to specific receptors rather than to particular neurotransmitters.

• Acetylcholine is one of the most common neurotransmitters in both invertebrates and vertebrates.

• Except in the heart, vertebrate neurons that form a synapse with muscle cells release acetylcholine as an excitatory transmitter.

• Acetylcholine binds to receptors on ligand-gated channels in the muscle cell, producing an EPSP.

• Nicotine binds to the same receptors, which are also found elsewhere in the PNS and in the CNS.

• Nicotine’s stimulant effects result from this affinity.

• Acetylcholine activity is terminated by hydrolysis by acetylcholinesterase, an enzyme in the synaptic cleft.

• Certain bacteria produce a toxin that specifically inhibits the presynaptic release of acetylcholine.

• This toxin is the cause of a rare but severe form of food poisoning called botulism.

• Untreated botulism is fatal because the muscles required for breathing fail to contract.

• Recently, the botulinum toxin has become a controversial tool in cosmetic surgery.

• Injections of the toxin, known as Botox, reduce wrinkles by blocking transmission at synapses that control facial muscles.

Acetylcholine has inhibitory rather than excitatory effects in regulating heart muscle.

• In the heart, acetylcholine released by neurons activates a signal transduction pathway.

• The G proteins in the pathway inhibit adenylyl cyclase and open K⁺ channels in the muscle cell membrane.

• Both effects reduce the rate at which cardiac muscle cells contract.

• Two amino acids serve as the major neurotransmitters in the vertebrate CNS: gamma aminobutyric acid (GABA) and glutamate.

• GABA is the neurotransmitter at most inhibitory synapses in the brain, where it produces IPSPs by increasing the permeability of the postsynaptic membrane to Cl^-.

• Glutamate, the most common neurotransmitter in the brain, is always excitatory.

• A third amino acid, glycine, acts at inhibitory synapses in parts of the CNS that lie outside of the brain.

• Several neuropeptides, relatively short chains of amino acids formed by cleavage of much larger proteins, serve as neurotransmitters that operate via signal transduction pathways.

• The neuropeptide substance P is a key excitatory neurotransmitter that mediates our perception of pain.

• Other neuropeptides, endorphins, act as natural analgesics to decrease pain perception.

• Candace Pert and Solomon Snyder discovered endorphins in the 1970s as an outcome of their research on the biochemistry of behavior.

• Pert and Snyder studied the activity of different drugs in the brain to demonstrate the existence of specific receptors for opiates, painkilling drugs such as morphine and heroin.

• In setting out to find any molecules normally present in the brain that could also activate these receptors, they identified endorphins.

• Endorphins are produced in the brain during times of physical or emotional stress, such as childbirth.

• In addition to relieving pain, endorphins decrease urine output, depress respiration, and produce euphoria, as well as other emotional effects.

• Because opiates bind to the same receptors as endorphins, opiates mimic endorphins and produce many of the same physiological effects.

• Biogenic amines are neurotransmitters derived from amino acids.

• The biogenic amine serotonin is synthesized from tryptophan.

• Several other biogenic amines, the catecholamines, are derived from tyrosine.

• One catecholamine, dopamine, acts only as a neurotransmitter.

• Two others—epinephrine and norepinephrine—act both as neurotransmitters and as hormones.

• Norepinephrine and acetylcholine are the two major neurotransmitters in the PNS of vertebrates.

• Acting through a G protein-coupled receptor, norepinephrine generates EPSPs in the autonomic nervous system, a branch of the PNS.

• In the CNS, biogenic amines are involved in modulating synaptic transmission.

• Dopamine and serotonin, released in the brain, affect sleep, mood, attention, and learning.

• LSD and mescaline produce hallucinations by binding to brain receptors for serotonin and dopamine.

• Biogenic amines have a central role in many nervous system disorders and treatments.

• Parkinson’s disease is associated with a lack of dopamine in the brain.

• Depression may be treated with drugs that increase the brain concentrations of biogenic amines.

• Prozac inhibits the uptake of serotonin after its release, thus increasing its effect.

• Some vertebrate neurons release dissolved gases, especially nitric oxide (NO) and carbon monoxide (CO), that act as local regulators.

• During male sexual arousal, certain neurons release NO into the erectile tissue of the penis.

• In response, smooth muscle cells in the blood vessel walls of the erectile tissue relax, allowing the blood vessels to dilate and fill the spongy erectile tissue with blood, producing an erection.

• Viagra inhibits an enzyme that slows the muscle-releasing effects of NO.

• Unlike most neurotransmitters, NO is not stored in cytoplasmic vesicles but is instead synthesized on demand.

• NO diffuses into neighboring target cells, produces a change, and is broken down—all within a few seconds.

• In many of its targets, including smooth muscle cells, NO stimulates an enzyme to synthesize a second messenger that directly affects cellular metabolism.

• CO is synthesized in small amounts in the human body.

• CO is generated by the enzyme heme oxygenase, found in some neurons in the brain and PNS.

• In the brain, CO regulates the release of hypothalamic hormones.

• In the PNS, CO acts as an inhibitory neurotransmitter that hyperpolarizes intestinal smooth muscle cells.