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10 Overview Overview of of Synaptic Synaptic Tr, Transmission Syn.apsesAre Either Electrical or Chemical Electrical Syn.apsesProvide Instantaneous Signal 1I:ansmission Gap-JunctionChannelsConnectCommunicating Cells at an ElectricalSynapse ElectricalTransmissionAllows the Rapid and SynchronousFiring of InterconnectedCells Gap JunctionsHave a Role in Glial Function and Disease Chemical SynapsesCan Amplify Signals ChemicalTransmittersBind to PostsynapticReceptors PostsynapticReceptorsGate Ion ChannelsEither Directly or Indirectly W HATGIVESNERVE CELLStheir special ability to communicate with one another so rapidly, over such great distances, and with such tremendous precision? We have already seen how signals are propagated within a neuron, from its dendrites and cell body to its axonal terminal. Beginning with this chapter we consider the cellular mechanismsfor signaling betweenneurons. The point at which one neuron communicates with another is called a synapse,and synaptic transmission is fundamental to many of the processeswe consider later in the book, such as perception, voluntary movement, and learning. Theaverageneuronformsabout 1000synapticconnections and receives even more, perhaps as many as 10,000connections. The Purkinje cell of the cerebellum receivesup to 100,000inputs. Although many of these connections are highly specialized, all neurons make use of one of two basic forms of synaptic transmission: electrical or chemical. Moreover, the strength of both forms of synaptic transmission can be enhanced or diminished by cellular activity. This pblsticityin nerve cells is crucial to memory and other higher brain functions. In the brain, electrical synaptic transmission is rapid and rather stereotyped. Electrical synapses are used primarily to send simple depolarizing signals; they do not lend themselvesto producing inhibitory actions or making long-lasting changes in the electrical properties of postsynaptic cells. In contrast, chemical synapses are capable of more variable signaling and thus can producemore complexbehaviors.They can mediate either excitatory or inhibitory actions in postsynaptic cells and produce electrical changes in the postsynaptic cell that last from milliseconds to many minutes. Chemical synapsesalso serve to amplify neuronal signals,sothat evena smallpresynapticnerveterminal can alter the responseof a large postsynaptic cell. Becausechemical synaptic transmission is so central to understanding brain and behavior, it is examined in detail in Chapters 11,12,and 13. Synapses Are Either Electrical or Chemical The term synapsewas introduced at the turn of the century by Charles Sherrington to describe the specialized zone of contact at which one neuron communicateswith another; this site had first been described histologically (at the level of light microscopy) by Ram6n y Cajal. Initially, all synapseswere thought to operate by means of electrical transmission. In the 1920s, however, Otto Loewi showed that acetylcholine (ACh), a chemicalcompound, conveys signals from the vagus nerve to the 176 Partm / ElementaryInteractionsBetweenNeurons:SynapticThansmission Table 10-1 Distinguishing Properties of Electrical and Chemical Synapses Type of synapse Distance between pre- and postsynaptic cell membranes Cytoplasmic continuity between pre- and postsynaptic cells Electrical 3.5nm Chemical 20-40nm Ultrastructural components Agent of transmission Synaptic delay Direction of transmission Yes Gap-junction channels Ion current Vtrtually absent Usually bidirectional No Presynaptic vesicles and active zones; postsynaptic receptors Chemical transmitter Significant: at least 0.3 IDS,usually 1-5 IDS or longer Unidirectional heart. Loewi's discovery in the heart provoked considerable debate in the 193Osover how chemical signals could generateelectrical activities at other synapses,including nerve-muscle synapses and synapses in the brain. Two schools of thought emerged, one physiological and the other pharmacological. Each championed a single mechanism for all synaptic transmission. The physiologists, led by John Eccles (Sherrington's student), argued that all synaptic transmission is electrical, that the action potential in the presynaptic neuron generates a current that flows passively into the postsynaptic cell. The pharmacologists, led by Henry Dale, argued that transmission is chemical, that the action potential in the presynaptic neuron leads to the release of a chemical substancethat in turn initiates current flow in the postsynaptic cell. A Current flow at electrical synapses When physiological techniques improved in the 19508and 1960sit becameclear that both forms of transmission exist. Although most synapsesuse a chemical transmitter, some operate purely by electrical means. Oncethe fine structure of synapses was made visible with the electron microscope, chemical and electrical synapseswere found to have different morphologies. At chemical synapsesneurons are separatedcompletely by a small space, the synaptic cleft. There is no continuity between the cytoplasm of one cell and the next. In contrast, at electrical synapses the pre- and postsynaptic cells communicate through special channels, the gapjunction channels,that serve as conduits between the cytoplasm of the two cells. The main functional properties of the two types of synapses are summarized in Table 10-1. The most important differences can be observed by injecting current B Current flow at chemical synapses I Presyneptjc Postsynaptic Figure10-1 Currentflows differently at electricaland chemical synapses. A. At an electrical synapsesome of the current injected into a presynapticcell escapesthrough resting ion channelsin the cell membrane.However, some current also flows into the postsynapticcell through specializedion channels.called gapjunction channels,that connect the cytoplasm of the pre- and postsynapticcells. B. At chemical synapsesall of the injected current escapes through ion channelsin the presynapticcell. However,the resulting depolarizationof the cell activates the releaseof neurotransmitter molecules packagedin synaptic vesicles (open circlesl, which then bind to receptors on the postsynapticcell. This binding opens ion channels,thus initiating a change in membrane potential in the postsynapticcell. Chapter10I Overviewof SynapticTransmission 177 I A Experimentalsetup PresYl18ptic neuron: Ieter8I gie~ fiber Current Injection Recordng ---- Iecording Cutr8nt~ injection Figure 10-2 Electrical synaptic transmission was first demonstrated to occur at the giant motor synapse in the crayfish. (Adaptedfrom Furshpanand Potter 1957 and 1959.) A. The presynapticneuron is the lateral giant fiber running down the nerve cord. The postsynaptic neuron is the motor fiber.which projectsfromthe cell bodyin the ganglionto the periphery.The electrodes for passing current and for recording voltage are placed within both the p(f~ and postsynapticcells. B. Transmissionat an electrical synapse is virtually instant&neous-the postsynapticresponsefollows presynapticstimulation in a fraction of a millisecond.The dashed line shows how the responsesof the two cells correspondin time. In contrast. at chemical synapsesthere ia a delay between the pre- and postsynaptic potentials (see Figure 1~7). j into the presynaptic cell to elicit a signal (Figure to-t). external membrane of the postsynaptic ceIL which has a I 1 C 1 c t t 14 C tJ tJ c D T it ti t1 P ta T 01 p; At both types of synapses the current flows outward acrossthe presynaptic cell membrane. This current deposits a positive charge on the inside of the presynaptic cell membrane, reducing its negative charge and thereby depolarizing the cell (seeChapter 8). At electrical synapses the gap-junction channels that connect the pre- and postsynaptic cells provide a low-resistance (high conductance) pathway for electrical current to flow between the two cells. Thus, some of the current injected in the presynaptic cell flows through these channels into the postsynaptic cell. This current deposits a positive charge on the inside of the membrane of the postsynaptic cell and depolarizes it. The current then flows out through resting ion channels in the postsynaptic cell (Figure to-tA). H the depolarization exceeds threshold, voltage-gated ion channels in the postsynaptic cell will open and generate an action potential. At chemical synapses there is no direct low-resistance pathway between the pre- and postsynaptic cells. Thus, current injected into a presynaptic cell flows out of the cell's resting channels into the synaptic cleft, the path of least resistance.Uttle or no current crossesthe high resistance(Figure 10-1B).Instead, the action potential in the presynaptic neuron initiates the release of a chemical transmitter, which diffuses acrossthe synaptic cleft to interact with receptors on the membrane of the postsynaptic cell. Receptor activation causesthe cell either to depolarize or to hyperpolarize. Electrical Synapses Provide Instantaneous Signal Transmission At electrical synapses the current that depoJarizesthe postsynaptic cell is generated directly by the voltagegated ion channels of the presynaptic cell. Thus these channels not only have to depolarize the presynaptic cell above the threshold for an action potential, they must also generate sufficient ionic current to produce a change in potential in the postsynaptic cell. To generate such a large current, the presynaptic terminal has to be large enough for its membrane to contain a large number of ion channels.At the same time, the postsynaptic cell has to be relatively small. This is becausea small cell has a higher input resistance(RiD)than a Iarsecell ArnI, 178 Part m/ ElementaryinteractiON BetweenNeurons:Synaptic Transmission ~ ~ ~ J Current pulse to L. presyneptic cell Volt8ge recorded \... In presynepticcell Agur. 10-3 Electrical transmission is graded and occurs even when the currents In the presynaptic cell are below the threshold for an ection potential. This can be demonstrated by depolarizingthe presynapticcell with a small outward current pulse. Current is passed by one electrode while the membranepotential is recorded with a second electrode. A subthresholddepolarizingstimulus causes a passive depolarization In the presynapticand postsynapticcells. (Outward, depolarizingcurrent is indicated by upward deflection.) according to Ohm's law (I1V" tJ x Rjn),will undergo a greater voltage change (11V) in response to a given presynaptic current (tJ). Electrical synaptic transmission was first described in the giant motor synapse of the crayfish, where the presynaptic fiber is much larger than the postsynaptic fiber (Figure to-2A). An action potential generated in the presynaptic fiber produces a depolarizing postsynaptic potential that is often large enough to discharge an action potential. The lIltency-the time between the presynaptic spike and the postsynaptic potential-is remarkably short (Figure to-2B). Such a short latency is incompatible with chemical transmission, which requires several biochemical steps: release of a transmitter from the presynaptic neuron, diffusion of the transmitter to the postsynaptic cell, binding of the transmitter to a specific receptor, and subsequentgating of ion channels (all described later in this chapter). Only current flowing directly from one cell to another can produce the near-instantaneous transmission observed at the giant motor synapse. Further evidence for electrical transmission is that the change in potential of the postsynaptic cell is directly related to the size and shape of the change in p0tential of the presynaptic cell. At an electrical synapse any amount of current in the presynaptic cell triggers a response in the postsynaptic cell. Even when a subthreshold depolarizing current is injected into the presynaptic neuron, current flows into the postsynaptic cell and depolarizes it (Figure 10-3).In contrast, at a chemical synapse the presynaptic current must reach the threshold for an action potential before the cell can releasetransmitter. Most electrical synapseswill transmit both depolarizing and hyperpolarizing currents. A presynaptic action potential that has a large hyperpolarizing afterpotential will produce a biphasic (depolarizinghyperpolarizing) changein potential in the postsynaptic cell. Transmission at electrical synapsesis similar to the passiveelectrotonic propagation of subthreshold electrical signals along axons (seeChapter 8) and therefore is often referred to as electrotonictransmission.Electrotonic transmission has been observed even at junctions where, unlike the giant motor synapse of the crayfish, the pre- and postsynaptic elements are similar in size. Because signaling between neurons at electrical synapsesdepends on the passive electrical properties at the synapse, such electrical synapses can be bidirectional, transmitting a depolarization signal equally well from either cell. Gap-junction ChannelsConnectCommunicating Cells at an Electrical Synapse Electrical transmission takes place at a specialized region of contact between two neurons termed the gap junction. At electrical synapsesthe separation between two neurons is much less (3.5 nm) than the normal, nonsynapticspace between neurons (20 nm). This narrow gap is bridged by the gap-junctiondulnnels,specialized protein structures that conduct the flow of ionic current from the presynaptic to the postsynaptic cell (Figure 10-4). All gap-junction channels consist of a pair of hemichannels, one in the presynaptic and the other in the postsynaptic cell. These hemichannels make contact in the gap between the two cell membranes, forming a continuous bridge between the cytoplasm of the two cells (Figure 10-4A). The pore of the channel has a large diameter of around 1.5 nm, and this large size permits small intracellular metabolites and experimental markers such as fluorescent dyes to pass between the two cells. Each hemichannel is called a connexon.A connexon is made up of six identical protein subunits, called connexins(Figure10-4B).Each connexin is involved in two sets of interactions. First, each connexin recognizesthe other five connexins to form a hemichannel. Second, each connexin of a hemichannel in one cell recognizes the extracellular domains of the apposing connexin of the hemichannel of the other cell to form the conducting channel that connectsthe two cells. ~ Chapter 10 / Overview of SynapticTransmission 179 <It'" ".. ,," ,,'" " ..' ,,' ",/' ~""..,; / Normal extracellular space Ch8meI formed bvporesin 88d1 membr8ne . 6 connexin subunits 1 connexon (hemich8nnell &ch 01 the 15connexins has .. membr8ne-spenning regions Cytopllsmic loops for regulation ExtraceIIulir Ip8C8 , Extracellular loops for hemophilic interactions Figure 10-4 A three-dimensionalmodelof the gap-junction channel, based on X-ray and electron diffraction studies. A. At electrical synapsestwo cells are structurally connected by gap-junctionchannels. A gap-junctionchannel is actuallya pair of hemichannels,one in each apposite cell, that match up in the gap junction through homophilicinteractions.The channelthus connects the cytoplasm of the two cells and provides a direct means of ion flow between the cells. This bridging of the cells is facilitated by a narrowingof the normal intercellularspace (20 nm) to only 3.5 nm at the gap junction. (Adaptedfrom Makowski et al. 1977.) Electron micrograph: The arrayof channels shown here was isolated from the membrane of a rat liver.The tissue has been negatively stained, a technique that darkensthe area aroundthe channelsand in the pores. Each channelappearshexagonalin outline. Magnification x 307,800. (Courtesyof N. Gilula.) B. Each hemichannel, or connexon, is made up of six identical protein subunits called connexins. Each connexin is about 7.5 nm long and spans the cell membrane. A single connexin is thought to have four membranErSpanning regions. The amino acid sequences of gapjunction proteins from many different kinds of tissue all show regions of similarity. In particular, four hydrophobic domains with a high degree of similarity among different tissues are presumed to be the regions of the protein structure that traverse the cell membrane. In addition, two extracellular regions that are also highly conserved in different tissues are thought to be involved in the homophilic matching of apposite hemichannels. C. The connexins are arranged in such a way that a pore is formed in the center of the structure. The resulting connexon, with an overall diameter of approximately 1.5-2 nm, has a characteristic hexagonal outline, as shown in the electron micrograph in A. The pore is opened when the subunits rotate about 0.9 nm at the cytoplasmic base in a clockwise direction. (From Unwin and Zampighi 1980.) 180 Part ill / ElementaryInteractionsBetweenNeurons: Synaptic Transmission Connexins from different tissues all belong to one large gene family. Each connexin subunit has four hydrophobic domains thought to span the cell membrane. These membrane-spanning domains in the gapjunction channelsof different tissuesare quite similar, as are the two extracellular domains thought to be involved in the homophilic recognition of the hemichannels of apposite cells (Figure lo-4C). On the other hand, the cytoplasmic regions of different connexins vary greatly, and this variation may explain why gap junctions in different tissuesare sensitive to different modulatory factors that control their opening and closing. For example, most gap-junction channels close in response to lowered cytoplasmic pH or elevated cytoplasmic CaH. These two properties serve to decouple damaged cells from other cells, since damaged cells contain elevated ea2+ and proton concentrations. At some specialized gap junctions the channels have voltagedependent gatesthat permit them to conduct depolarizing current in only one direction, from the presynaptic cell to the postsynaptic cell. These junctions are called rectifying synapses.(The crayfish giant motor synapse is an example.) Finally, neurotransmitters released from nearby chemical synapsescan modulate the opening of gap-junction channels through intracellular metabolic reactions (seeChapter 13). How do the channels open and close?One suggestion is that, to exposethe channel's pore, the six connexins in a hemichannel rotate slightly with respect to one another, much like the shutter in a camera. The concerted tilting of each connexin by a few Angstroms at one end leads to a somewhat larger displacement at the other end (Figure lO-4B). As we saw in Chapter 7, conformational changesin ion channels may be a common mechanism for opening and closing the channels. Electrical Transmission Allows the Rapid and Synchronous Firing of Interconnected Cells Why is it useful to have electrical synap~? As we have seen, transmission across electrical synapses is extremely rapid becauseit results from the direct flow of current from the presynaptic neuron to the postsynaptic cell. And speed is important for certain escape responses.For example, the tail-flip response of goldfish is mediated by a giant neuron (known as Mauthner's cell) in the brain stem, which receives input from sensory neurons at electrical synapses. These electrical synapsesrapidly depolarize the Mauthner's cell, which in turn activates the motor neurons of the tail, allowing the fish to escapequickly from danger. Electrical transmission is also useful for connecting large groups of neurons. Becausecurrent flows across the membranes of all electrically coupled cells at the same time, several small cells can act coordinately as one large cell. Moreover, becauseof the electrical coupling between the cells, the effective resistanceof the coupled network of neurons is smaller than the resistance of an individual cell. As we have seenfrom Ohm's law (AV = AI X R), the lower the resistanceof a neuron, the smaller the depolarization produced by an excitatory synaptic current. Thus, electrically coupled cells require a larger synaptic current to depolarize them to threshold, compared with the current that would be necessaryto fire an individual cell. This property makes it difficult to cause them to fire action potentials. Once this high threshold is surpassed, however, electrically coupled cells tend to fire synchronously becauseactive Na + currents generated in one cell are rapidly transmitted to the other cells. Thus, a behavior controlled by a group of electrically coupled cells has an important adaptive advantage: It is triggered explosively in an all-or-none manner. For example, when seriously perturbed, the marine snail Aplysia releasesmassive clouds of purple ink that provide a protective screen.This stereotypic behavior is mediated by three electrically coupled, high-threshold motor cells that innervate the ink gland. Once the threshold for firing is exceededin these cells, they fire synchronously (Figure 10-5). In certain fish, rapid eye movements (called saccades)are also mediated by electrically coupled motor neurons acting synchronously. In addition to providing speed or synchrony in neuronal signaling, electrical synapses also may transmit metabolicsignals between cells. Because gap-junction channels are relatively large and nonselective, they readily allow inorganic cations and anions to flow through. In fact, gap-junction channelsare large enough to allow moderate-sized organic compounds (less than 1000 molecular weight~ch as the second messengers IP3 (inositol triphosphate), cAMP, and even small peptides-to pass from one cell to the next. Gap Junctions Have a Role in Glial Function and Disease Gap junctions are found between glial cells as well as between neurons. In glia the gap junctions seemto mediate both intercellular and intracellular communication. The role of gap junctions in signaling between glial cells is best observed in the brain, where individual astrocytes are connected to each other through gap junctions, forming a glial cell network. Electrical stimulation of neuronal pathways in brain slices can trigger a rise of intracellular Ca2+in certain astrocytes.This produces a wave of intracellular Ca2+throughout the astrocytenet- Chapter 10 / Overview of SynapticTransmission Figure 10-5 Electrically coupled motor neurons firing together can produce instantaneous behaviors. The behavior illustrated here is the release of a protective cloud of ink by the marine snail AplysiB.(Adaptedfrom Carew and Kandel 1976.) A. Sensoryneuronsfrom the tail ganglion form synapseswith three motor neurons that project to the ink gland.The motor neuronsare interconnectedby means of electricalsynapses. B. A train of stimuli applied to the tail produces a synchronized discharge in all three motor neurons. 1. When the motor neurons are at rest the stimulus triggers a train of identical action potentials in all three cells. This synchronous activity in the motor neurons results in the release of ink. 2. When the cells are hyperpolarized the stimulus cannot trigger action potentials, because the cells are too far from their threshold level. Under these conditions the inking response is blocked. A Neural circuit of the inking response B Motor cell responses to tail stimulation 1 Cellsat rest R8IeIse of Ink A c 2 Cells hyperpolarized ........ ofink 181 182 Part ill / ElementaryInteractionsBetweenNeurons: Synaptic Transmission work, traveling at a rate of around 1 JLn'l/ms. These Ca2+ waves are believed to propagate by diffusion through gap-junction channels. Although the precise function of such Ca2+ waves is not known, their existence clearly suggeststhat glia may play an active role in signaling in the brain. Evidence that gap junctions enhance communication within a single glial cell is found in Schwann cells of the myelin sheath.As we have seenin Chapter 4, successivelayers of myelin are connectedby gap junctions, which may serve to hold the layers of myelin together. However, they may also be important for passing small metabolitesand ions acrossthe many intervening layers of myelin, from the outer perinuclear region of the Schwann cell down to the inner periaxonal region. The importance of these gap-junction channels is underscored by certain neurological genetic diseases.For example, the X chromosome-linked form of CharcotMarie-Tooth disease, which causes demyelination, results from single mutations in one of the connexin genes(connexin32)expressedin the Schwann cell. Such mutations prevent this connexin from forming functional gap-junction channels essential for the normal flow of metabolites in the Schwann cell. termed exocytosis. The transmitter molecules then diffuse across the synaptic cleft and bind to their receptorson the postsynaptic cell membrane.This in turn activatesthe receptors, leading to the opening or closing of ion channels. The resulting ionic flux alters the membrane conductance and potential of the postsynaptic cell (Figure 10-7). These several steps account for the synaptic delay at chemical synapses, a delay that can be as short as 0.3 ms but often lasts several milliseconds or longer. Although chemical transmission lacks the speedof electrical synapses,it has the important property of amplification. With the discharge of just one synaptic vesicle, several thousand molecules of transmitter stored in that vesicle are released. lYPically, only two molecules of transmitter are required to open a single postsynaptic ion channel. Consequently, the action of one synaptic vesicle can open thousands of ion channels in the postsynaptic cell. In this way a small presynaptic nerve terminal, which generatesonly a weak electrical current, can releasethousands of transmitter molecules that can depolarize even a large postsynaptic cell. Chemical Synapses Can Amplify Signals In contrast to the situation at electrical synapses,there is no structural continuity between pre- and postsynaptic neurons at chemical synapses. In fact, at chemical synapsesthe region separating the pre- and postsynaptic cells-the synaptic cleft-is usually slightly wider (20-40 nm), sometimessubstantially wider, than the adjacent nonsynaptic intercellular space (20 nm). As a result, chemical synaptic transmission depends on the release of a neurotransmitter from the presynaptic neuron. A neurotransmitteris a chemical substancethat will bind to specific receptors in the postsynaptic cell membrane. At most chemical synapses,transmitter release occurs from presynaptic termiruzls, specialized swellings of the axon. The presynaptic terminals contain discrete collections of synapticvesicles,each of which is filled with several thousand molecules of a specific transmitter (Figure 10-6). The synaptic vesicles cluster at regions of the membrane specialized for releasing transmitter called active zones.During discharge of a presynaptic action potential Ca2+ enters the presynaptic terminal through voltagegated Ca2+channelsat the active zone. The rise in intracellular Ca2+ concentration causes the vesicles to fuse with the presynaptic membrane and thereby release their neurotransmitter into the synaptic cleft, a process ~ Figure 10-8 The synaptic cleft separates the presynaptic and postsynaptic cell membranes at chemical synapses. This electron micrographshows the fine structure of a presynaptic terminal in the cerebellum.The large dark structures are mitochondria.The many round bodies are vesicles that contain neurotransmitter.The fuzzy dark thickenings along the presynaptic side of the cleft (arrows) are specializedareas,called active zones,that are thought to be docking and releasesites for vesicles. (Courtesyof J. E. Heuser and T. S. Reese.) r Chapter 10 / Overview of SynapticTransmission Action nerve potential ten}'linal in opens ~.channels cr.entrytaunl ReceptOl'-chlnnett open, Na + ent8f8 the po8taynIptic Y8IicIe fusion and trlnlfT1itl8r........ cell end v8IicI88 recyde Presynaptic ection potenti8l PTe8yneptic: mV ~ ~\ 0 ~ -55 -70 .. r;,/I>. . .... Excitatory poetsyneptic potential ~~ rrN --[= -70 183 .0... e .. . 0 nerve t8rminII .. . . R8c8pt0r- .chInneI '. . , NI+ Post- aynIpIic CIII H , I'ftI Rgure 10-7 Synaptic transmission at chemical synapses involves several steps. An action potential arrivingat the terminal of a presynapticaxon causes voltage-gatedCa2+channels at the active zone to open. The influx of Ca2+producesa high concentrationof Ca2+near the active zone. which in tum causesvesicles containing neurotransmitterto fuse with the presynapticcell membraneand releasetheir contents into the synapticcleft (a process termed exocytosis).The released neurotransmittermolecules then diffuse acrossthe synaptic Chemical Transmitters Bind to Postsynaptic Receptors Chemical synaptic transmission can be divided into two steps: a transmitting step, in which the presynaptic cell releasesa chemical messenger,and a receptivestep, in which the transmitter binds to the receptor molecules in the postsynaptic cell. The transmitting process resembles the release processof an endocrine gland, and chemical synaptic transmission can be seenas a modified form of hormone secretion.80th endocrine glands and presynaptic terminals releasea chemical agent with a signaling function, and both are examples of regulated secretion (Chapter 4). Similarly, both endocrine glands and neurons are usually some distance from their target cells. There is one important difference, however. The hormone released by the gland travels through the blood stream until it interacts with all cells that contain an appropriate receptor.A neuron, on the other hand, usually communicatesonly with specific cells, the cells with which it forms synapses.Communication consistsof a presynaptic neuron sending an action potential down its axon to the axon terminal, where the electrical signal triggers cleft and bind to specific receptors on the post-synapticmembrane.These receptorscause ion channelsto open (or close). thereby changingthe membraneconductanceand membrane potential of the postsynapticcell. The complex processof chemical synaptic transmissionis responsiblefor the delay between action potentials in the pre- and post-synapticcells ~ pared with the virtually instantaneoustransmissionof signalsat electrical synapses(see Figure 10-28).The gray filaments rep- resentthe dockingandreleasesitesof the activezone. the focused releaseof the chemical transmitter onto a targetcell.Thus the chemical signal travels only a small distance to its target. Neuronal signaling, therefore, has two special features:It is fast and precisely directed. To accomplish this highly directed or focused release,most neurons have specialized secretory machinery, the active zones. In neurons without active zones the distinction between neuronal and hormonal transmission becomesblUrred. For example, the neurons in the autonomic nervous system that innervate smooth muscle reside at some distance from their postsynaptic cells and do not have specialized release sites in their terminals. Synaptic transmission between these cells is slower and more diffuse. Furthermore, at one set of terminals a transmitter can be releasedat an active zone, as a conventional transmitter acting directly on neighboring cells; at another locus it can be releasedin a less focused way as a modulator, producing a more diffuse action; and at a third locus it can be releasedinto the blood stream as a neurohormone. Although a variety of chemicals serve as neurotransmitters, including both small molecules and peptides (seeChapter 15), the action of a transmitter in the ~ 184 Part ill / ElementaryInteractions BetweenNeurons: Synaptic Transmission A Directgating B Indirect gating Receptor Pore " Transmitter Pore 0Wtn8I Transmitter I Receptor Effector function Extracellular side G protein side \ cAMP Effector AA AAA GTP ~ p AdeI1yIyt cycIae ,:,~fUnction -,r. ~MP kinase ExtnIceiluler side a T a I p Figure10-8 Neurotransmittersact either directly or indirectly on ion channelsthat regulatecurrent flow in neurons. A. Direct gating of ion channels is mediated by ionotropic receptors. This type of receptor is an integral part of the same macromolecule that forms the channel it regulates and thus is sometimes referred to as a receptor-<:hannel or ligand-gated channel. Many ionotropic receptors are composed of five subunits, each of which is thought to contain four membranespanning a-helical regions (see Chapters 11, 12). B. Indirect gating is mediated by activation of metabotropic receptors. This type of receptor is distinct from the ion channels postsynaptic cell does not depend on the chemical properties of the transmitter but rather on the properties of the receptors that recognize and bind the transmitter. For example, acetylcholine (ACh) can excite some postsynaptic cells and inhibit others, and at still other cells it can produce both excitation and inhibition. It is the receptor that determines whether a cholinergic synapse is excitatory or inhibitory and whether an ion channel will be activated directly by the transmitter or indirectly through a second messenger. Within a group of closely related animals a given transmitter substancebinds to conserved families of receptors and is associated with specific physiological functions. For example, in vertebrates ACh produces synaptic excitation at the neuromuscular junction by acting on a special type of excitatory ACh receptor. It also slows the heart by acting on a special type of inhibitory ACh receptor. The notion of a receptor was introduced in the late it regulates. The receptor activates a GTP-binding protein (G protein), which in tum activates a second-messenger cascade that modulates channel activity. Here the G protein stimulates adenylyl cyclase, which converts ATP to cAMP. The cAMP activates the cAMP-dependent protein kinase (cAMP-kinase), which phosphorylates the channel (P), leading to a change in function. (The action of second messengers in regulating ion channels is described in detail in Chapter 13.) The typical metabotropic receptor is composed of a single subunit with seven membrane-spanning a-helical regions that bind the ligand within the plane of the membrane. nineteenth century by the German bacteriologist Paul Ehrlich to explain the selectiveaction of toxins and other pharmacological agents and the great specificity of immunological reactions.In 1900Ehrlich wrote, "Chemical substancesare only able to exercisean action on the tissue elementswith which they areable to establishan intimate chemical relationship. . . . [This relationship] must be specific. The [chemical] groups must be adapted to one another. . . as lock and key." In 1906the English pharmacologistJohnLangley postulated that the sensitivity of skeletal muscle to curare and nicotine was caused by a "receptive molecule." A theory of receptor function was later developed by Langley's students (in particular, Eliot Smith and Henry Dale),a development that was basedon concurrent studies of enzyme kinetics and cooperative interactions between small molecules and proteins. As we shall seein the next chapter,Langley's "receptive molecule" hasbeenisolated and characterizedas the ACh receptor of the neuromuscularjunction. Chapter 10 / Overview of SynapticTransmission All receptorsfor chemicaltransmittershave two biochemicalfeaturesin common: 1. Theyare membrane-spanning proteins. The region exposedto the external environment of the cell recognizes and binds the transmitter from the presynaptic cell. 2 They carry out an effector function within the target cell. The receptors typically influence the opening or closing of ion channels. lions lasting seconds to minutes. These slower actions can modulate behavior by altering the excitability of neurons and the strength of the synaptic connections of the neural circuitry mediating behavior. Such modulatory synaptic pathways often act as crucial reinforcing pathways in the process of learning. Eric Eric R. R. Kandel Kandel Steven StevenA. A. Siegelbaum Siegelbaum PostsynapticReceptorsGateIon Channels Either Directly or Indirectly Chemical neurotransmitters act either directly or indirectly in controlling the opening of ion channels in the postsynaptic cell. The two classesof transmitter actions are mediated by receptor proteins derived from different gene families. Receptors that gate ion channels directly, such as the nicotinic ACh receptor at the neuromuscular junction, are integral membrane proteins. Several subunits comprise a single macromolecule that contains both an extracellular domain that forms the receptor for transmitter and a membrane-spanning domain that forms an ion channel (Figure 10-8A). Such receptors are often referred to as ionotropic receptors.Upon binding neurotransmitter the receptor undergoes a conformational change that results in the opening of the channel The actions of ionotropic receptors, also called receptorchannels or ligand-gated channels, are discussed in greater detail in Chapter 11. Receptorsthat gate ion channels indirectly, like the several types of norepinephrine or serotonin receptors at synapsesin the cerebral cortex, are macromolecules that are distinct from the ion channels they affect. These receptors act by altering intracellular metabolic reactions and are often referred.to as metabotropic receptors. Activation of these receptors very often stimulates the production of secondmessengers,small freely diffusible intracellular metabolites such as cAMP and diacylglyceroL Many such second messengersactivate protein kinases,enzymes that phosphorylate different substrate proteins. In many instancesthe protein ldnases directly phosphorylate ion channels,leading to their opening or closing. The actions of the metabotropic receptor are examined in detail in Chapter 13. Ionotropic and metabotropic receptors have different functions. The ionotropic receptors produce relatively fast synaptic actions lasting only milliseconds. Theseare commonly found in neural circuits that mediate rapid behaviors, such as the stretch receptor reflex. The metabotropic receptorsproduce slower synaptic ac- 185 185 Selected Readings Bennett MY. 1997. Gap junctions as electrical synapses. J Neurocytol 26:349-366. Eccles Je. 1976. From electrical to chemical transmission in the central nervous system. 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