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Home , Electrical synapse, Synapse, Synaptic vesicle

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OverviewOverview ofof SynapticSynaptic Tr,Transmission

Syn.apsesAre Either Electrical or Chemical electrical or chemical. Moreover, the strength of both Electrical Syn.apsesProvide Instantaneous Signal forms of synaptic transmission can be enhanced or di- 1I:ansmission minished by cellular activity. This pblsticity in cells Gap-JunctionChannels Connect Communicating Cells at is crucial to and other higher functions. an Electrical In the brain, electrical synaptic transmission is ElectricalTransmission Allows the Rapid and rapid and rather stereotyped. Electrical are SynchronousFiring of InterconnectedCells used primarily to send simple depolarizing signals; Gap JunctionsHave a Role in Glial Function and Disease they do not lend themselves to producing inhibitory ac- tions or making long-lasting changes in the electrical Chemical SynapsesCan Amplify Signals properties of postsynaptic cells. In contrast, chemical Chemical TransmittersBind to PostsynapticReceptors synapses are capable of more variable signaling and PostsynapticReceptors Gate Ion ChannelsEither Directly thus can produce more complex behaviors.They can or Indirectly mediate either excitatory or inhibitory actions in post- synaptic cells and produce electrical changes in the postsynaptic that last from milliseconds to many minutes. Chemical synapsesalso serve to amplify neu- W HATGIVES NERVE CELLS their special ability to ronal signals,so that evena smallpresynaptic nerve ter- communicate with one another so rapidly, minal can alter the responseof a large postsynaptic cell. over such great distances, and with such Becausechemical synaptic transmission is so central to tremendous precision? We have already seen how sig- understanding brain and behavior, it is examined in de- nals are propagated within a , from its tail in Chapters 11, 12, and 13. and cell body to its axonal terminal. Beginning with this chapter we consider the cellular mechanisms for signal- ing betweenneurons. The point at which one neuron Synapses Are Either Electrical or Chemical communicates with another is called a synapse,and synaptic transmission is fundamental to many of the The term synapsewas introduced at the turn of the cen- processeswe consider later in the book, such as percep- tury by Charles Sherrington to describe the specialized tion, voluntary movement, and learning. zone of contact at which one neuron communicateswith Theaverage neuron forms about 1000synaptic con- another; this site had first been described histologically nections and receives even more, perhaps as many as (at the level of light microscopy) by Ram6n y Cajal. Ini- 10,000connections. The of the tially, all synapseswere thought to operate by means of receivesup to 100,000inputs. Although many of these electrical transmission. In the 1920s, however, Otto connections are highly specialized, all make Loewi showed that (ACh), a chemicalcom- use of one of two basic forms of synaptic transmission: pound, conveys signals from the vagus nerve to the 176 Partm / ElementaryInteractions Between Neurons: Synaptic Thansmission

Table 10-1 Distinguishing Properties of Electrical and Chemical Synapses

Distance between Cytoplasmic pre- and continuity Type of postsynaptic cell between pre- and Ultrastructural Agent of Synaptic Direction of synapse membranes postsynaptic cells components transmission delay transmission

Electrical 3.5nm Yes Gap-junction Ion current Vtrtually Usually channels absent bidirectional Chemical 20-40nm No Presynaptic Chemical Significant: Unidirec- vesicles and transmitter at least 0.3 tional active zones; IDS,usually postsynaptic 1-5 IDS receptors or longer

heart. Loewi's discovery in the heart provoked consid- When physiological techniques improved in the erable debate in the 193Osover how chemical signals 19508and 1960sit becameclear that both forms of trans- could generateelectrical activities at other synapses,in- mission exist. Although most synapsesuse a chemical cluding nerve-muscle synapses and synapses in the transmitter, some operate purely by electrical means. brain. Oncethe fine structure of synapses was made visible Two schools of thought emerged, one physiological with the , chemical and electrical and the other pharmacological. Each championed a sin- synapseswere found to have different morphologies. At gle mechanism for all synaptic transmission. The physi- chemical synapsesneurons are separatedcompletely by ologists, led by John Eccles (Sherrington's student), ar- a small space, the synaptic cleft. There is no continuity gued that all synaptic transmission is electrical, that the between the cytoplasm of one cell and the next. In con- in the presynaptic neuron generates a trast, at electrical synapses the pre- and postsynaptic current that flows passively into the postsynaptic cell. cells communicate through special channels, the gap- The pharmacologists, led by Henry Dale, argued that junction channels,that serve as conduits between the cy- transmission is chemical, that the action potential in the toplasm of the two cells. presynaptic neuron to the release of a chemical The main functional properties of the two types of substancethat in turn initiates current flow in the post- synapses are summarized in Table 10-1. The most im- synaptic cell. portant differences can be observed by injecting current

A Current flow at electrical synapses B Current flow at chemical synapses

I

Presyneptjc Postsynaptic

Figure10-1 Currentflows differently at electricaland chem- B. At chemical synapsesall of the injected current escapes ical synapses. through ion channels in the presynapticcell. However,the re- A. At an some of the current injected into a sulting depolarizationof the cell activates the releaseof neuro- presynapticcell escapes through resting ion channels in the transmitter molecules packagedin synaptic vesicles (open cir- .However, some current also flows into the clesl, which then bind to receptors on the postsynapticcell. postsynapticcell through specializedion channels. called gap- This binding opens ion channels,thus initiating a change in junction channels,that connect the cytoplasm of the pre- and in the postsynaptic cell. postsynapticcells. Chapter10 I Overviewof SynapticTransmission 177

I A Experimentalsetup

Current PresYl18ptic neuron: Injection Ieter8I gie~ fiber

Recordng----

Iecording

Cutr8nt~ injection

Figure 10-2 Electrical synaptic transmission was first voltage are placed within both the p(f~ and postsynapticcells. demonstrated to occur at the giant motor synapse in the B. Transmissionat an electrical synapse is virtually instant&- crayfish. (Adaptedfrom Furshpanand Potter 1957 and 1959.) neous-the postsynapticresponse follows presynapticstimula- A. The presynapticneuron is the lateral giant fiber running tion in a fraction of a millisecond.The dashed line shows how down the nerve cord. The postsynaptic neuron is the motor the responsesof the two cells correspond in time. In contrast. fiber.which projectsfrom the cell bodyin the ganglionto the at chemical synapsesthere ia a delay between the pre- and I periphery.The electrodes for passing current and for recording 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 1 At both types of synapses the current flows outward high resistance(Figure 10-1B).Instead, the action poten- C acrossthe presynaptic cell membrane. This current de- tial in the presynaptic neuron initiates the release of a

1 posits a positive charge on the inside of the presynaptic chemical transmitter, which diffuses acrossthe synaptic c cell membrane, reducing its negative charge and cleft to interact with receptors on the membrane of the t thereby depolarizing the cell (seeChapter 8). postsynaptic cell. activation causesthe cell ei- At electrical synapses the gap-junction channels ther to depolarize or to hyperpolarize. t that connect the pre- and postsynaptic cells provide a 14 low-resistance (high conductance) pathway for electri- C cal current to flow between the two cells. Thus, some of Electrical Synapses Provide Instantaneous tJ the current injected in the presynaptic cell flows Signal Transmission tJ through these channels into the postsynaptic cell. This c current deposits a positive charge on the inside of the At electrical synapses the current that depoJarizesthe D membrane of the postsynaptic cell and depolarizes it. postsynaptic cell is generated directly by the voltage- T The current then flows out through resting ion channels gated ion channels of the presynaptic cell. Thus these it in the postsynaptic cell (Figure to-tA). H the depolariza- channels not only have to depolarize the presynaptic ti tion exceeds threshold, voltage-gated ion channels in cell above the threshold for an action potential, they t1 the postsynaptic cell will open and generate an action must also generate sufficient ionic current to produce a

P potential. change in potential in the postsynaptic cell. To generate At chemical synapses there is no direct low-resis- such a large current, the presynaptic terminal has to be ta tance pathway between the pre- and postsynaptic cells. large enough for its membrane to contain a large num- T Thus, current injected into a presynaptic cell flows out ber of ion channels. At the same time, the postsynaptic 01 of the cell's resting channels into the synaptic cleft, the cell has to be relatively small. This is becausea small cell

p; path of least resistance.Uttle or no current crossesthe has a higher input resistance(RiD) than a Iarsecell ArnI, 178 Part m/ Elementary interactiON BetweenNeurons: SynapticTransmission

~ Current pulse to and depolarizes it (Figure 10-3).In contrast, at a chemi- ~ L. presyneptic cell cal synapse the presynaptic current must reach the threshold for an action potential before the cell can re- ~ Volt8ge recorded J \... In presynepticcell leasetransmitter. Most electrical synapseswill transmit both depolar- izing and hyperpolarizing currents. A presynaptic action potential that has a large hyperpolarizing afterpotential will produce a biphasic (depolarizing- hyperpolarizing) changein potential in the postsynaptic cell. Transmission at electrical synapsesis similar to the passive electrotonic propagation of subthreshold electri- Agur. 10-3 Electrical transmission is graded and occurs even when the currents In the presynaptic cell are below cal signals along (seeChapter 8) and therefore is the threshold for an ection potential. This can be demon- often referred to as electrotonictransmission. Electrotonic strated by depolarizingthe presynapticcell with a small out- transmission has been observed even at junctions ward current pulse. Current is passed by one electrode while where, unlike the giant motor synapse of the cray- the membranepotential is recorded with a second electrode. fish, the pre- and postsynaptic elements are similar in A subthresholddepolarizing causes a passive depolar- ization In the presynapticand postsynaptic cells. (Outward, size. Because signaling between neurons at electrical depolarizingcurrent is indicated by upward deflection.) synapsesdepends on the passive electrical properties at the synapse, such electrical synapses can be bidirec- tional, transmitting a signal equally well from either cell.

Gap-junction ChannelsConnect Communicating Cells at an Electrical Synapse according to Ohm's law (I1V" tJ x Rjn),will undergo a greater voltage change (11V) in response to a given Electrical transmission takes place at a specialized re- presynaptic current (tJ). gion of contact between two neurons termed the gap Electrical synaptic transmission was first described junction. At electrical synapses the separation between in the giant motor synapse of the crayfish, where the two neurons is much less (3.5 nm) than the normal, non- presynaptic fiber is much larger than the postsynaptic synapticspace between neurons (20 nm). This narrow fiber (Figure to-2A). An action potential generated in gap is bridged by the gap-junction dulnnels,specialized the presynaptic fiber produces a depolarizing post- structures that conduct the flow of ionic current synaptic potential that is often large enough to dis- from the presynaptic to the postsynaptic cell (Figure charge an action potential. The lIltency-the time be- 10-4). tween the presynaptic spike and the postsynaptic All gap-junction channels consist of a pair of potential-is remarkably short (Figure to-2B). hemichannels,one in the presynaptic and the other in the Such a short latency is incompatible with chemical postsynaptic cell. These hemichannels make contact in transmission, which requires several biochemical steps: the gap between the two cell membranes, forming a release of a transmitter from the presynaptic neuron, continuous bridge between the cytoplasm of the two diffusion of the transmitter to the postsynaptic cell, cells (Figure 10-4A). The pore of the channel has a large binding of the transmitter to a specific receptor, and diameter of around 1.5 nm, and this large size permits subsequentgating of ion channels (all described later in small intracellular metabolites and experimental mark- this chapter). Only current flowing directly from one ers such as fluorescent dyes to pass between the two cell to another can produce the near-instantaneous cells. transmission observed at the giant motor synapse. Each hemichannel is called a .A connexon Further evidence for electrical transmission is that is made up of six identical protein subunits, called con- the change in potential of the postsynaptic cell is di- nexins(Figure 10-4B). Each is involved in two rectly related to the size and shape of the change in p0- sets of interactions. First, each connexin recognizes the tential of the presynaptic cell. At an electrical synapse other five to form a hemichannel. Second, any amount of current in the presynaptic cell triggers a each connexin of a hemichannel in one cell recognizes response in the postsynaptic cell. Even when a sub- the extracellular domains of the apposing connexin of threshold depolarizing current is injected into the pre- the hemichannel of the other cell to form the conducting synaptic neuron, current flows into the postsynaptic cell channel that connectsthe two cells. Chapter 10 / Overview of Synaptic Transmission 179

~""..,;

Figure 10-4 A three-dimensionalmodel of the gap-junction channel, based on X-ray and electron diffraction studies. A. At electrical synapsestwo cells are struc- / Normal turally connected by gap-junctionchannels. extracellular A gap-junctionchannel is actuallya pair of space hemichannels,one in each apposite cell, that match up in the through homophilic interactions.The channelthus con- nects the cytoplasm of the two cells and pro- vides a direct means of ion flow between the cells. This bridging of the cells is facilitated by a Ch8meI formed bvporesin narrowing of the normal intercellularspace 88d1 membr8ne (20 nm) to only 3.5 nm at the gap junction. (Adaptedfrom Makowski et al. 1977.) Electron micrograph: The array of channels shown here was isolated from the membrane of a rat liver. The tissue has been negatively stained, a technique that darkensthe area around the channelsand in the pores. Each 6 connexin subunits . &ch 01 the 15connexins 1 connexon (hemich8nnell channelappears hexagonal in outline. Magnifi- has .. membr8ne-spenning cation x 307,800. (Courtesyof N. Gilula.) regions B. Each hemichannel, or connexon, is made up Cytopllsmic loops of six identical protein subunits called connex- for regulation ins. Each connexin is about 7.5 nm long and spans the cell membrane. A single connexin is thought to have four membranErSpanning re- gions. The sequences of gap- junction from many different kinds of tissue all show regions of similarity. In particu- ExtraceIIulir lar, four hydrophobic domains with a high de- Ip8C8 gree of similarity among different tissues are Extracellular loops for , hemophilic interactions 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 match- ing of apposite hemichannels. C. The connexins are arranged in such a way that a pore is formed in the center of the struc- ture. The resulting connexon, with an overall di- ameter of approximately 1.5-2 nm, has a char- acteristic 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 / Elementary InteractionsBetween Neurons: Synaptic Transmission

Connexins from different tissues all belong to one the membranes of all electrically coupled cells at the large gene family. Each connexin subunit has four same time, several small cells can act coordinately as hydrophobic domains thought to span the cell mem- one large cell. Moreover, becauseof the electrical cou- brane. These membrane-spanning domains in the gap- pling between the cells, the effective resistance of the junction channelsof different tissuesare quite similar, as coupled network of neurons is smaller than the resis- are the two extracellular domains thought to be in- tance of an individual cell. As we have seenfrom Ohm's volved in the homophilic recognition of the hemichan- law (AV = AI X R), the lower the resistanceof a neuron, nels of apposite cells (Figure lo-4C). On the other hand, the smaller the depolarization produced by an excita- the cytoplasmic regions of different connexins vary tory synaptic current. Thus, electrically coupled cells re- greatly, and this variation may explain why gap junc- quire a larger synaptic current to depolarize them to tions in different tissues are sensitive to different modu- threshold, compared with the current that would be latory factors that control their opening and closing. necessaryto fire an individual cell. This property makes For example, most gap-junction channels close in it difficult to cause them to fire action potentials. Once response to lowered cytoplasmic pH or elevated cyto- this high threshold is surpassed, however, electrically plasmic CaH. These two properties serve to decouple coupled cells tend to fire synchronously becauseactive damaged cells from other cells, since damaged cells con- Na + currents generated in one cell are rapidly transmit- tain elevated ea2+ and proton concentrations. At some ted to the other cells. specialized gap junctions the channels have voltage- Thus, a behavior controlled by a group of electri- dependent gates that permit them to conduct depolariz- cally coupled cells has an important adaptive advan- ing current in only one direction, from the presynaptic tage: It is triggered explosively in an all-or-none man- cell to the postsynaptic cell. These junctions are called ner. For example, when seriously perturbed, the marine rectifying synapses.(The crayfish giant motor synapse is snail releasesmassive clouds of purple ink that an example.) Finally, released from provide a protective screen.This stereotypic behavior is nearby chemical synapsescan modulate the opening of mediated by three electrically coupled, high-threshold gap-junction channels through intracellular metabolic motor cells that innervate the ink gland. Once the reactions (seeChapter 13). threshold for firing is exceeded in these cells, they fire How do the channels open and close?One sugges- synchronously (Figure 10-5). In certain fish, rapid eye tion is that, to exposethe channel's pore, the six connex- movements (called saccades)are also mediated by elec- ins in a hemichannel rotate slightly with respect to one trically coupled motor neurons acting synchronously. another, much like the shutter in a camera. The con- In addition to providing speed or synchrony in neu- certed tilting of each connexin by a few Angstroms at ronal signaling, electrical synapses also may transmit one end leads to a somewhat larger displacement at the metabolicsignals between cells. Because gap-junction other end (Figure lO-4B). As we saw in Chapter 7, con- channels are relatively large and nonselective, they formational changesin ion channels may be a common readily allow inorganic cations and anions to flow mechanism for opening and closing the channels. through. In fact, gap-junction channels are large enough to allow moderate-sized organic compounds (less than 1000 molecular weight~ch as the second messen- Electrical Transmission Allows the Rapid and gers IP3 ( triphosphate), cAMP, and even small Synchronous Firing of Interconnected Cells peptides-to pass from one cell to the next. Why is it useful to have electrical synap~? As we have seen, transmission across electrical synapses is ex- Gap Junctions Have a Role in Glial tremely rapid becauseit results from the direct flow of Function and Disease current from the presynaptic neuron to the postsynaptic cell. And speed is important for certain escape re- Gap junctions are found between glial cells as well as sponses.For example, the tail-flip response of goldfish between neurons. In the gap junctions seem to me- is mediated by a giant neuron (known as Mauthner's diate both intercellular and intracellular communica- cell) in the brain stem, which receives input from sen- tion. The role of gap junctions in signaling between glial sory neurons at electrical synapses. These electrical cells is best observed in the brain, where individual as- synapsesrapidly depolarize the Mauthner's cell, which trocytes are connected to each other through gap junc- in turn activates the motor neurons of the tail, allowing tions, forming a glial cell network. Electrical stimulation the fish to escapequickly from danger. of neuronal pathways in brain slices can trigger a rise of Electrical transmission is also useful for connecting intracellular Ca2+ in certain . This produces a large groups of neurons. Becausecurrent flows across wave of intracellular Ca2+throughout the net- Chapter 10 / Overview of SynapticTransmission 181

Figure 10-5 Electrically coupled motor neurons firing together can produce instantaneous behaviors. The behavior illustrated here is the release of a protec- tive cloud of ink by the marine snail AplysiB.(Adapted from Carew and Kandel 1976.) A. Sensory neurons from the tail form synapseswith three motor neurons that project to the ink gland. The motor neuronsare interconnected by means of electrical synapses. B. A train of stimuli applied to the tail pro- duces a synchronized discharge in all three motor neurons. 1. When the motor neurons are at rest the stimulus triggers A of the inking response 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 hyperpolar- ized the stimulus cannot trigger action potentials, because the cells are too far from their threshold level. Under these conditions the inking response is blocked.

B Motor cell responses to tail stimulation

1 Cellsat rest 2 Cells hyperpolarized

R8IeIse ...... of Ink ofink

A

c 182 Part ill / Elementary Interactions BetweenNeurons: Synaptic Transmission

work, traveling at a rate of around 1 JLn'l/ms. These termed . Ca2+ waves are believed to propagate by diffusion The transmitter molecules then diffuse across the through gap-junction channels. Although the precise synaptic cleft and bind to their receptors on the postsyn- function of such Ca2+ waves is not known, their exis- aptic cell membrane. This in turn activates the receptors, tence clearly suggests that glia may play an active role leading to the opening or closing of ion channels. The in signaling in the brain. resulting ionic flux alters the membrane conductance Evidence that gap junctions enhance communica- and potential of the postsynaptic cell (Figure 10-7). tion within a single glial cell is found in Schwann cells These several steps account for the synaptic delay of the sheath.As we have seen in Chapter 4, suc- at chemical synapses, a delay that can be as short as cessivelayers of myelin are connected by gap junctions, 0.3 ms but often lasts several milliseconds or longer. Al- which may serve to hold the layers of myelin together. though chemical transmission lacks the speed of electri- However, they may also be important for passing small cal synapses,it has the important property of amplifica- metabolites and ions acrossthe many intervening layers tion. With the discharge of just one , of myelin, from the outer perinuclear region of the several thousand molecules of transmitter stored in that down to the inner periaxonal region. The vesicle are released. lYPically, only two molecules of importance of these gap-junction channels is under- transmitter are required to open a single postsynaptic scored by certain neurological genetic diseases.For ex- . Consequently, the action of one synaptic ample, the X chromosome-linked form of Charcot- vesicle can open thousands of ion channels in the post- Marie-Tooth disease, which causes demyelination, synaptic cell. In this way a small presynaptic nerve ter- results from single mutations in one of the connexin minal, which generatesonly a weak electrical current, genes(connexin32) expressed in the Schwann cell. Such can releasethousands of transmitter molecules that can mutations prevent this connexin from forming func- depolarize even a large postsynaptic cell. tional gap-junction channels essential for the normal flow of metabolites in the Schwann 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 postsynap- tic cells-the synaptic cleft-is usually slightly wider (20-40 nm), sometimes substantially wider, than the ad- jacent nonsynaptic intercellular space (20 nm). As a re- sult, chemical synaptic transmission depends on the re- lease of a from the presynaptic neuron. A neurotransmitteris a chemical substance that will bind to specific receptors in the postsynaptic cell membrane. At most chemical synapses,transmitter re- lease occurs from presynaptic termiruzls, specialized swellings of the . The presynaptic terminals contain discrete collections of synaptic vesicles,each of which is filled with several thousand molecules of a specific transmitter (Figure 10-6). The synaptic vesicles cluster at regions of the mem- Figure 10-8 The synaptic cleft separates the presynaptic brane specialized for releasing transmitter called active and postsynaptic cell membranes at chemical synapses. zones.During discharge of a presynaptic action potential This electron micrographshows the fine structure of a presyn- Ca2+ enters the presynaptic terminal through voltage- aptic terminal in the cerebellum.The large dark structures are gated Ca2+channels at the . The rise in intra- mitochondria.The many round bodies are vesicles that contain neurotransmitter.The fuzzy dark thickenings along the presy- cellular Ca2+ concentration causes the vesicles to fuse naptic side of the cleft (arrows) are specializedareas, called ac- with the presynaptic membrane and thereby release tive zones, that are thought to be docking and releasesites for their neurotransmitter into the synaptic cleft, a process vesicles. (Courtesyof J. E. Heuser and T. S. Reese.) r Chapter 10 / Overview of Synaptic Transmission 183

Action potential in cr.entry taunl ReceptOl'-chlnnett open, nerve ten}'linal Y8IicIe fusion and Na+ ent8f8 the po8taynIptic opens ~.channels trlnlfT1itl8r...... cell end v8IicI88 recyde Presynaptic ection potenti8l PTe8yneptic: nerve mV t8rminII ~ ~\ 0 0 ~ .0 . e -55 .. -70 . . r;,/I>...... R8c8pt0r- Excitatory . . . '. .chInneI poetsyneptic potential . rrN ~~ , Post- NI+ aynIpIic --[= CIII -70 H , I'ftI

Rgure 10-7 Synaptic transmission at chemical synapses in- cleft and bind to specific receptors on the post-synapticmem- volves several steps. An action potential arrivingat the termi- brane.These receptors cause ion channelsto open (or close). nal of a presynapticaxon causes voltage-gatedCa2+ channels thereby changingthe membrane conductanceand membrane at the active zone to open. The influx of Ca2+produces a high potential of the postsynapticcell. The complex process of concentrationof Ca2+near the active zone. which in tum chemical synaptic transmission is responsiblefor the delay be- causesvesicles containing neurotransmitter to fuse with the tween action potentials in the pre- and post-synapticcells ~ presynapticcell membrane and release their contents into the pared with the virtually instantaneoustransmission of signalsat synaptic cleft (a process termed exocytosis).The released electrical synapses(see Figure 10-28).The gray filaments rep- neurotransmittermolecules then diffuse across the synaptic resentthe dockingand release sites of the activezone.

Chemical Transmitters Bind the focused release of the chemical transmitter onto a to Postsynaptic Receptors targetcell. Thus the chemical signal travels only a small Chemical synaptic transmission can be divided into two distance to its target. Neuronal signaling, therefore, has steps: a transmitting step, in which the presynaptic cell two special features: It is fast and precisely directed. releasesa chemical messenger,and a receptivestep, in To accomplish this highly directed or focused re- which the transmitter binds to the receptor molecules in lease,most neurons have specialized secretory machin- the postsynaptic cell. ery, the active zones. In neurons without active zones The transmitting process resembles the release the distinction between neuronal and hormonal trans- process of an endocrine gland, and chemical synaptic mission becomes blUrred. For example, the neurons in transmission can be seenas a modified form of hormone the autonomic that innervate smooth secretion.80th endocrine glands and presynaptic termi- muscle reside at some distance from their postsynaptic nals releasea chemical agent with a signaling function, cells and do not have specialized release sites in their and both are examples of regulated secretion (Chapter terminals. Synaptic transmission between these cells is 4). Similarly, both endocrine glands and neurons are slower and more diffuse. Furthermore, at one set of ter- usually some distance from their target cells. There is minals a transmitter can be releasedat an active zone, as one important difference, however. The hormone re- a conventional transmitter acting directly on neighbor- leased by the gland travels through the blood stream ing cells; at another locus it can be releasedin a less fo- until it interacts with all cells that contain an appropri- cused way as a modulator, producing a more diffuse ac- ate receptor. A neuron, on the other hand, usually com- tion; and at a third locus it can be releasedinto the blood municates only with specific cells, the cells with which it stream as a neurohormone. forms synapses.Communication consistsof a presynap- Although a variety of chemicals serve as neuro- tic neuron sending an action potential down its axon to transmitters, including both small molecules and pep- the , where the electrical signal triggers tides (seeChapter 15), the action of a transmitter in the 184 Part ill / ElementaryInteractions BetweenNeurons: Synaptic Transmission

A Directgating B Indirect gating

Receptor Pore Pore

Transmitter I Transmitter 0Wtn8I " Receptor Effector Extracellular function side

side

cAMP AA Effector GTP ~ \ AAA p AdeI1yIyt cycIae - ,:,~fUnction -,r. ~MPkinase

ExtnIceiluler side

a T a I p

Figure10-8 Neurotransmittersact either directly or indi- it regulates. The receptor activates a GTP-binding protein (G rectly on ion channelsthat regulatecurrent flow in neu- protein), which in tum activates a second-messenger cascade rons. that modulates channel activity. Here the G protein stimulates A. Direct gating of ion channels is mediated by ionotropic re- adenylyl cyclase, which converts ATP to cAMP. The cAMP acti- ceptors. This type of receptor is an integral part of the same vates the cAMP-dependent protein kinase (cAMP-kinase), macromolecule that forms the channel it regulates and thus is which phosphorylates the channel (P), leading to a change in sometimes referred to as a receptor-<:hannel or ligand-gated function. (The action of second messengers in regulating ion channel. Many ionotropic receptors are composed of five sub- channels is described in detail in Chapter 13.) The typical units, each of which is thought to contain four membrane- metabotropic receptor is composed of a single subunit with spanning a-helical regions (see Chapters 11, 12). seven membrane-spanning a-helical regions that bind the ligand within the plane of the membrane. B. Indirect gating is mediated by activation of metabotropic re- ceptors. This type of receptor is distinct from the ion channels

postsynaptic cell does not depend on the chemical prop- nineteenth century by the German bacteriologist Paul erties of the transmitter but rather on the properties of Ehrlich to explain the selectiveaction of toxins and other the receptors that recognize and bind the transmitter. pharmacological agents and the great specificity of im- For example, acetylcholine (ACh) can excite some post- munological reactions.In 1900Ehrlich wrote, "Chemical synaptic cells and inhibit others, and at still other cells it substancesare only able to exercisean action on the tissue can produce both excitation and inhibition. It is the re- elementswith which they are able to establishan intimate ceptor that determines whether a synapse is chemical relationship. . . . [This relationship] must be excitatory or inhibitory and whether an ion channel will specific. The [chemical] groups must be adapted to one be activated directly by the transmitter or indirectly another. . . as lock and key." In 1906the English phar- through a second messenger. macologist John Langley postulated that the sensitivity of Within a group of closely related a given skeletal muscle to and nicotine was caused by a transmitter substancebinds to conserved families of re- "receptive molecule." A theory of receptor function was ceptors and is associated with specific physiological later developed by Langley's students (in particular, Eliot functions. For example, in ACh produces Smith and Henry Dale),a development that was basedon synaptic excitation at the by concurrent studies of enzyme kinetics and cooperative acting on a special type of excitatory ACh receptor. It interactions between small molecules and proteins. As also slows the heart by acting on a special type of in- we shall seein the next chapter,Langley's "receptive mol- hibitory ACh receptor. ecule" has been isolated and characterizedas the ACh re- The notion of a receptor was introduced in the late ceptor of the neuromuscular junction.

~ Chapter 10 / Overview of SynapticTransmission 185185

All receptorsfor chemical transmittershave two lions lasting seconds to minutes. These slower actions biochemicalfeatures in common: can modulate behavior by altering the excitability of neurons and the strength of the synaptic connections of 1. Theyare membrane-spanning proteins. The region the neural circuitry mediating behavior. Such modula- exposed to the external environment of the cell rec- tory synaptic pathways often act as crucial reinforcing ognizes and binds the transmitter from the pre- pathways in the process of learning. synaptic cell. 2 They carry out an effector function within the tar- get cell. The receptors typically influence the open- ing or closing of ion channels. EricEric R.R. KandelKandel StevenStevenA.A. SiegelbaumSiegelbaum PostsynapticReceptors Gate Ion Channels Either Directly or Indirectly Chemical neurotransmitters act either directly or indi- rectly in controlling the opening of ion channels in the postsynaptic cell. The two classesof transmitter actions are mediated by receptor proteins derived from differ- Selected Readings ent gene families. Bennett MY. 1997. Gap junctions as electrical synapses. Receptors that gate ion channels directly, such as J Neurocytol 26:349-366. the nicotinic ACh receptor at the neuromuscular junc- Eccles Je. 1976. From electrical to chemical transmission in tion, are integral membrane proteins. Several subunits the . The closing address of the Sir comprise a single macromolecule that contains both an Henry Dale Centennial Symposium. Notes Rec R Sac Lond 30-.219-230. extracellular domain that forms the receptor for trans- Furshpan BI, Potter DD. 1959.Thmsmission at the giant mo- mitter and a membrane-spanning domain that forms an tor synapses of the crayfish. J Physiol (Lond) 145:289-325. ion channel (Figure 10-8A). Such receptors are often re- Goodenough DA, Go1iger JA, Paul DL. 1996. Connexins, ferred to as ionotropic receptors.Upon binding neuro- , and intercellular communication. Ann Rev transmitter the receptor undergoes a conformational Biochem 65:475-502. change that results in the opening of the channel The Jesse1l'I'M, Kandel ER. 1993. Synaptic transmission: a bi- actions of ionotropic receptors, also called receptor- directional and a self-modifiable form of cell-cell commu- channels or ligand-gated channels, are discussed in nication. Ce1l72(Suppl):1-30. greater detail in Chapter 11. Unwin N. 1993.Neurotransmitter action: opening of ligand- Receptors that gate ion channels indirectly, like the gated ion channels. Ce1l72(Suppl):31-41. several types of or receptors References at synapsesin the , are macromolecules that are distinct from the ion channels they affect. These Beyer Ee, Paul DL, GoodenoughDA. 1987.Connexin43: a protein from rat heart homologous to a gap junction pr0- receptors act by altering intracellular metabolic reac- tein from liver. J Cell Bioi 105:2621-2629. tions and are often referred.to as metabotropicreceptors. Bruzzone It White lW, Scherer 55, Fischbeclc KH, Paul Activation of these receptors very often stimulates the DL. 1994. Null mutations of connexin 32 in patients production of secondmessengers, small freely diffusible with x-linked Charcot-Marie- Tooth disease. Neuron intracellular metabolites such as cAMP and diacylglyc- 13:1~1260. eroL Many such second messengersactivate protein ki- Carew 1}, Kandel ER. 1976. 1Wo functional effects of de- nases,enzymes that phosphorylate different substrate creased conductance EPSP's:synaptic augmentation and proteins. In many instances the protein ldnases directly increased electrotonic coupling. Science192:15(}-153. phosphorylate ion channels, leading to their opening or Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith 51. 1990. closing. The actions of the metabotropic receptor are ex- Glutamate induces calcium waves in cultured astrocytes: amined in detail in Chapter 13. long-range glial signaling. Science247:470-473. Dale H. 1935. Pharmacology and nerve-endings. Proc R Sac Ionotropic and metabotropic receptors have differ- Med (Lond) 28:319-332. ent functions. The ionotropic receptors produce rela- Eckert R. 1988. Propagation and transmission of signals. In: tively fast synaptic actions lasting only milliseconds. Physiology:Mechtmisms tmd AdJIptations,3m ed, pp. Theseare commonly found in neural circuits that medi- 134-176.New York: Freeman. ate rapid behaviors, such as the stretch receptor reflex. Ehrlich P. 1900. On immunity with special reference to cell The metabotropic receptors produce slower synaptic ac- life. Croo1UanLect ProcR SocLand 66:424-448. 186 Part ill / IDementaryInteractions BetweenNeurons: Synaptic Transmission

Furshpan BI, Potter 00.1957. Mechanism of nerve-impulse physiology:A SourceBook, pp. 478-485.New York: Holt, transmission at a crayfish synapse. Nature 180:342-343. Rinehart and Wmston. Heuser JE,Reese 'IS. 1977. Structure of the synapse. In: ER Makowski L, Caspar OLD, Phillips WC, Baker TS, Kandel (ed), Handbookof Physiology:A CritiCllI, Comprehen- Goodenough OA. 1984.Gap junction structures. VI. Vari- sive Presentationof PhysiologiCilIKnowledge and Concepts, ation and conservation in connexon conformation and Sect. 1, The Nervous System.Vol. 1, Cellular of Neu- packing. Biophys J 45:208-218. rons, Part 1, pp. 261-294. Bethesda,MD: American Physi- Pappas GO, Waxman SG. 1972. Synaptic fine structure-- ological Society. morphological correJates of chemical and electrotonic JasloveSW, Brink PRo1986. The mechanism of rectification at transmission. In: GO Pappas, OP Purpura (eds). Structure the electrotonic motor giant synapse of the crayfish. and Function of Synapses,pp. 1-43. New York: Raven. Nature 323:63-65. Ram6n y Cajal S. 1894.La fine structure des centres nerveux. Langley IN. 1906.On nerve endings and on special excitable Proc R Sac Land 55:444-468. substancesin cells. Proc R Soc Lond B BioI Sci 78:170-194. Ram6n y Cajal S. 1911.Hisrologie du SysthneNerveux de Loewi 0, Navratil E. 1926. Ober humorale Ubertragbarkeit l'Homme & des VerMbres,Vol. 2. L Azoulay (transl). Paris: der Herznervenwirkung. X. Mitteilung: iiber das Schick- Maloine; 1955.Reprint. Madrid: Instituto Ram6n y Cajal. sa! des Vagusstoffs. Pfliigers Arch. 214:6'78-688; 1972. Sherrington C. 1947.The Integrative Action of the NervousSys- 'Ii'anslated in: On the humoral propagation of cardiac tem,2nd ed. New Haven: Yale Univ. Press. nerve action. Communication X. The fate of the vagus Unwin PNT, Zampighi G. 1980.Structure of the junction be- substance. In: I Cooke, M Lipkin Jr (eds). Cellular Neuro- tween communicating cells. Nature 283:545-549.