During excitatory synaptic transmission at an electrical synapse, voltage-gated ion channels in the presynaptic cell generate the current that depolarizes the postsynaptic cell. Thus these channels not only depolarize the presynaptic cell above the threshold for an action potential but also generate sufficient ionic current to produce a change in potential in the postsynaptic cell.
To generate such a large current, the presynaptic terminal must be big enough for its membrane to contain many ion channels. At the same time, the postsynaptic cell must be relatively small. This is because a small cell has a higher input resistance (Rin) than a large cell and, according to Ohm's law (ΔV = I × Rin), undergoes a greater voltage change (ΔV) in response to a given presynaptic current (I).
Electrical synaptic transmission was first described by Edwin Furshpan and David Potter in the giant motor synapse of the crayfish, where the presynaptic fiber is much larger than the postsynaptic fiber (Figure 8–2A). An action potential generated in the presynaptic fiber produces a depolarizing postsynaptic potential that often exceeds the threshold to fire an action potential. At electrical synapses, the synaptic delay—the time between the presynaptic spike and the postsynaptic potential—is remarkably short (Figure 8–2B).
Electrical synaptic transmission was first demonstrated at the giant motor synapse in the crayfish.
(Adapted, with permission, from Furshpan and Potter 1957 and 1959.)
A. The lateral giant fiber running down the nerve cord is the presynaptic neuron. The giant motor fiber, which projects from the cell body in the ganglion to the periphery, is the postsynaptic neuron. Electrodes for passing current and for recording voltage are placed within the pre- and postsynaptic cells.
B. Transmission at an electrical synapse is virtually instantaneous—the postsynaptic response follows presynaptic stimulation in a fraction of a millisecond. The dashed line shows how the responses of the two cells correspond in time. At chemical synapses there is a delay (the synaptic delay) between the pre- and postsynaptic potentials (see Figure 8–8).
Such a short latency is not possible with chemical transmission, which requires several biochemical steps: release of a transmitter from the presynaptic neuron, diffusion of transmitter molecules to the postsynaptic cell, binding of transmitter to a specific receptor, and subsequent gating of ion channels (all described later in this chapter). Only current passing directly from one cell to another can produce the near-instantaneous transmission observed at the giant motor synapse.
Another feature of electrical transmission is that the change in potential of the postsynaptic cell is directly related to the size and shape of the change in potential of the presynaptic cell. Even when a weak subthreshold depolarizing current is injected into the presynaptic neuron, some current enters the post-synaptic cell and depolarizes it (Figure 8–3). In contrast, at a chemical synapse the current in the presynaptic cell must reach the threshold for an action potential before it can release transmitter and elicit a response in the postsynaptic cell.
Electrical transmission is graded and occurs even when the current in the presynaptic cell is below the threshold for an action potential.
This can be demonstrated by depolarizing the presynaptic cell with a small current pulse through one electrode while the membrane potential is recorded with a second electrode. A subthreshold depolarizing stimulus causes a passive depolarization in the presynaptic and postsynaptic cells. (Depolarizing or outward current is indicated by an upward deflection.)
Most electrical synapses can transmit both depolarizing and hyperpolarizing currents. A presynaptic action potential with a large hyperpolarizing afterpotential produces a biphasic (depolarizing-hyperpolarizing) change in potential in the postsynaptic cell. Signal transmission at electrical synapses is similar to the passive propagation of subthreshold electrical signals along axons (see Chapter 6) and therefore is also referred to as electrotonic transmission. At some specialized gap junctions the channels have voltage-dependent gates that 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.)
Cells at an Electrical Synapse Are Connected by Gap-Junction Channels
The specialized region of contact between two neurons at an electrical synapse is termed the gap junction. Here the separation between the two neurons (4 nm) is much less than the normal nonsynaptic space between neurons (20 nm). This narrow gap is bridged by the gap-junction channels, specialized protein structures that conduct ionic current from the presynaptic to the postsynaptic cell.
A gap-junction channel consists of a pair of hemichannels, or connexons, one in the presynaptic and the other in the postsynaptic cell membrane. These hemichannels thus form a continuous bridge that provides a direct communication path between the two cells (Figure 8–4). The pore of the channel has a large diameter of approximately 1.5 nm, which permits inorganic ions and small organic molecules and experimental markers such as fluorescent dyes to pass between the two cells.
A three-dimensional model of the gap-junction channel, based on X-ray and electron diffraction studies.
A. The electrical synapse, or gap junction, is composed of numerous specialized channels that span the membranes of two neurons. These gap-junction channels allow current to pass directly from one cell to the other. The array of channels shown in the electron micrograph was isolated from the membrane of a rat liver. The tissue has been negatively stained, a technique that darkens the area around the channels and in the pores. Each channel appears hexagonal in outline. Magnification × 307,800. (Reproduced, with permission, from N. Gilula.)
B. A gap-junction channel is actually a pair of hemichannels, one in each apposite cell that connects the cytoplasm of the two cells. (Adapted, with permission, from Makowski et al. 1977.)
C. Each hemichannel, or connexon, is made up of six identical subunits called connexins. Each connexin is approximately 7.5 nm long and spans the cell membrane. A single connexin has intracellular N- and C-termini, including a short intra-cellular N-terminal α-helix (NTH), and four membrane-spanning α-helixes (1–4). There are regions of similarity in the amino acid sequences of gap-junction proteins from many different kinds of tissue. These include the transmembrane helixes and the extracellular regions, which are involved in the homophilic matching of apposite hemichannels.
D. The connexins are arranged in such a way that a pore is formed in the center of the structure. The resulting connexon, with a pore diameter of approximately 1.5 to 2 nm, has a characteristic hexagonal outline, as shown in part A. In some gap-junction channels the pore is opened when the subunits rotate approximately 0.9 nm at the cytoplasmic base in a clockwise direction. (Reproduced, with permission, from Unwin and Zampighi 1980.)
Each hemichannel or connexon is composed of six identical subunits, called connexins. Connexins in different tissues are encoded by a large gene family containing more than 20 members. All connexin sub-units have an intracellular N- and C-terminus with four interposed α-helixes that span the cell membrane (Figure 8–4C). Many gap-junction channels in different cell types are formed by the products of different connexin genes and thus respond differently to modulatory factors that control their opening and closing. For example, although most gap-junction channels close in response to lowered cytoplasmic pH or elevated cytoplasmic Ca2+, the sensitivity of different channel isoforms to these factors varies widely. This pH and Ca2+-dependent closing of gap-junction channels plays an important role in the decoupling of damaged cells from healthy cells, because damaged cells contain elevated Ca2+ levels and a high concentration of protons. Finally, neurotransmitters released from nearby chemical synapses can modulate the opening of gap-junction channels through intracellular metabolic reactions (see Chapter 11).
The three-dimensional structure of a gap-junction channel formed by the human connexin 26 subunit has recently been determined by X-ray crystallography. This structure shows in detail how the membrane-spanning α-helixes assemble to form the central pore of the channel and how the extracellular loops connecting the transmembrane helixes interdigitate to connect the two hemichannels (Figure 8–5). The pore is lined with polar residues that facilitate the movement of ions. An N-terminal α-helix may serve as the voltage gate of the connexin 26 channel, plugging the cytoplasmic mouth of the pore in the closed state. A separate gate at the extracellular side of the channel, formed by the extracellular loop connecting the first two membrane helixes, has been inferred from functional studies. This loop gate is thought to close isolated hemichannels that are not docked to a hemichannel partner in the apposing cell.
High-resolution three-dimensional structure of a gap-junction channel.
All structures were determined by X-ray crystallography of gap-junction channels formed by the human connexon 26 subunit. (Reproduced, with permission, from Maeda et al., 2009.)
A. Left: Diagram of an intact gap-junction channel showing the pair of apposed hemichannels in the pre- and postsynaptic cells. Middle: High-resolution structure of a single connexin subunit showing the presence of four transmembrane α-helixes (1–4) and a short N-terminal helix (NTH). The orientation of the subunit corresponds to that of the yellow subunit in the diagram to the left. Right: Bottom-up view looking into a hemichannel from the cytoplasm. Each of the six subunits has a different color. The helixes of the yellow subunit are numbered. The orientation corresponds to that of the yellow hemichannel in the diagram at left, following a 90° rotation toward the viewer.
B. Two side views of the gap-junction channel in the plane of the membrane show the two apposed hemichannels. The orientation is the same as in the panel of part A. Left: Cross-section through the channel shows the internal surface of the channel pore. Blue indicates positively charged surfaces, and red indicates negatively charged surfaces. The green mass inside the pore at the cytoplasmic entrance (funnel) is thought to represent the channel gate formed by the N-terminal helix. Right: A side view of the channel shows each of the six connexin subunits in the same color scheme as in part A. The entire gap-junction channel is approximately 9 nm wide by 15 nm tall.
Electrical Transmission Allows the Rapid and Synchronous Firing of Interconnected Cells
How are electrical synapses useful? As we have seen, transmission across electrical synapses is extremely rapid because it results from the direct passage of current between cells. Speed is important for escape responses. For example, the tail-flip response of goldfish is mediated by a giant neuron in the brain stem (known as the Mauthner cell), which receives sensory input at electrical synapses. These electrical synapses rapidly depolarize the Mauthner cell, which in turn activates the motor neurons of the tail, allowing rapid escape from danger.
Electrical transmission is also useful for orchestrating the actions of large groups of neurons. Because current crosses the membranes of all electrically coupled cells at the same time, several small cells can act coordinately as one large cell. Moreover, because of the electrical coupling between the cells, the effective resistance of the coupled network of neurons is smaller than the resistance of an individual cell. Thus, from Ohm's law, the synaptic current required to fire electrically coupled cells is larger than that necessary to fire an individual cell. That is, electrically coupled cells have a higher firing threshold. Once this high threshold is surpassed, however, electrically coupled cells fire synchronously because voltage-activated Na+ currents generated in one cell are very rapidly conducted to other cells.
Thus a behavior controlled by a group of electrically coupled cells has an important adaptive advantage: It is triggered explosively. For example, when seriously perturbed, the marine snail Aplysia releases massive clouds of purple ink that provide a protective screen. This stereotypic behavior is mediated by three electrically coupled motor cells that innervate the ink gland. Once the action potential threshold is exceeded in these cells, they fire synchronously (Figure 8–6). In certain fish, rapid eye movements (called saccades) are also mediated by electrically coupled motor neurons firing together. Gap junctions are also important in the mammalian brain, where the synchronous firing of electrically coupled inhibitory interneurons generates synchronous, high-frequency oscillations.
Electrically coupled motor neurons firing together can produce synchronous behaviors.
(Adapted, with permission, from Carew and Kandel 1976.)
A. In the marine snail Aplysia sensory neurons from the tail ganglion form synapses with three motor neurons that innervate the ink gland. The motor neurons are interconnected by electrical synapses.
B. A train of stimuli applied to the tail produces a synchronized discharge in all three motor neurons that results in the release of ink.
In addition to providing speed or synchrony in neuronal signaling, electrical synapses also can transmit metabolic signals between cells. Because gap-junction channels are relatively large and nonselective, they conduct a variety of inorganic cations and anions, including the second messenger Ca2+, and even allow moderate-sized organic compounds (less than 1,000 Da molecular weight)—such as the second messengers inositol 1,4,5-trisphosphate (IP3), cyclic adenosine monophosphate (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 formed between glial cells as well as between neurons. In glia the gap junctions mediate both intercellular and intracellular communication. In the brain individual astrocytes are connected to each other through gap junctions, which mediate communication between them, forming a glial cell network. Electrical stimulation of neuronal pathways in brain slices can release neurotransmitters that trigger a rise in intracellular Ca2+ in certain astrocytes. This produces a wave of Ca2+ that propagates at a rate of approximately 1 μm/s, traveling from astrocyte to astrocyte by diffusion through gap-junction channels. Although the precise function of the waves is unknown, their existence suggests that glia may play an active role in signaling in the brain.
Gap-junction channels also enhance communication within certain glial cells, the Schwann cells that produce the myelin sheath of axons in the peripheral nervous system. Successive layers of myelin formed by a single Schwann cell are connected by gap junctions. These gap junctions may help to hold the layers of myelin together and promote the passage of small metabolites and ions across the many layers of myelin. The importance of the Schwann cell gap-junction channels is underscored by certain genetic diseases. For example, the X chromosome-linked form of Charcot-Marie-Tooth disease, a demyelinating disorder, is caused by single mutations in a connexin gene (connexin 32) expressed in the Schwann cell that blocks gap-junction channel function. Inherited mutations that prevent the function of a connexin expressed in the cochlea (connexin 26) underlie up to half of all instances of congenital deafness. This connexin normally forms gap-junction channels that are important for fluid secretion in the inner ear.