kThe release of neurotransmitter. Depolarization of the nerve terminal by the action potential opens voltage-gated calcium channels. Increased intracellular Ca2+ initiates fusion of synaptic vesicles with the presynaptic membrane, resulting in the release of neurotransmitter molecules into the synaptic cleft and binding with postsynaptic receptors.
Synaptic Transmission Usually Occurs via Chemical Neurotransmitters
At chemical synapses, a space called the synaptic cleft separates the presynaptic axon terminal from the postsynaptic cell (Fig. 3.8). The presynaptic terminal is packed with vesicles containing chemical neurotransmitters that are released into the synaptic cleft when an action potential enters the terminal. Once released, the chemical neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic cell. The binding of the transmitter to its receptor leads to the opening (or closing) of specific ion channels, which, in turn, alter the membrane potential of the postsynaptic cell.
The release of neurotransmitters from the presynaptic terminal begins with the invasion of the action potential into the axon terminal (Fig. 3.9). The depolarization of the terminal by the action potential causes the activation of voltage-gated Ca2+ channels. The electrochemical gradients for Ca2+ result in forces that drive Ca2+ into the terminal. This increase in intracellular ionized calcium causes a fusion of vesicles, containing neurotransmitters, with the presynaptic membrane at active zones. The neu-rotransmitters are then released into the cleft by exocyto-sis. Increasing the amount of Ca2+ that enters the terminal increases the amount of transmitter released into the synap-tic cleft. The number of transmitter molecules released by any one exocytosed vesicle is called a quantum, and the total number of quanta released when the synapse is activated is called the quantum content. Under normal conditions, quanta are fixed in size but quantum content varies, particularly with the amount of Ca2+ that enters the terminal.
The way in which the entry of Ca2 + leads to the fusion of the vesicles with the presynaptic membrane is still being elucidated. It is clear that there are several proteins involved in this process. One hypothesis is that the vesicles are anchored to cytoskeletal components in the terminal by synapsin, a protein surrounding the vesicle. The entry of Ca2 + ions into the terminal is thought to result in phos-phorylation of this protein and a decrease in its binding to the cytoskeleton, releasing the vesicles so they may move to the synaptic release sites.
Other proteins (rab GTP-binding proteins) are involved in targeting synaptic vesicles to specific docking sites in the presynaptic terminal. Still other proteins cause the vesicles to dock and bind to the presynaptic terminal membrane,- these proteins are called SNARES and are found on both the vesicle and the nerve terminal membrane (called v-SNARES or t-SNARES, respectively). Tetanus toxin and botulinum toxin exert their devastating effects on the nervous system by disrupting the function of SNARES, preventing synaptic transmission. Exposure to these toxins can be fatal because the failure of neurotransmission between neurons and the muscles involved in breathing results in respiratory failure. To complete the process begun by Ca2+ entry into the nerve terminal, the docked and bound vesicles must fuse with the membrane and create a pore through which the transmitter may be released into the synaptic cleft. The vesicle membrane is then removed from the terminal membrane and recycled within the nerve terminal.
Once released into the synaptic cleft, neurotransmitter molecules exert their actions by binding to receptors in the postsynaptic membrane. These receptors are of two types. In some, the receptor forms part of an ion channel,- in others, the receptor is coupled to an ion channel via a G protein and a second messenger system. In receptors associated with a specific G protein, a series of enzyme steps is initiated by binding of a transmitter to its receptor, producing a second messenger that alters intracellular functions over a longer time than for direct ion channel opening. These membrane-bound enzymes and the second messengers they produce inside the target cells include adenylyl cy-clase, which produces cAMP,- guanylyl cyclase, which produces cGMP,- and phospholipase C, which leads to the formation of two second messengers, diacylglycerol and inositol trisphosphate (see Chapter 1).
When a transmitter binds to its receptor, membrane conductance changes occur, leading to depolarization or hyperpolarization. An increase in membrane conductance to Na+ depolarizes the membrane. An increase in membrane conductance that permits the efflux of K+ or the influx of Cl" hyperpolarizes the membrane. In some cases, membrane hyperpolarization can occur when a decrease in membrane conductance reduces the influx of Na+. Each of these effects results from specific alterations in ion channel function, and there are many different ligand-gated and voltage-gated channels.
Integration of Postsynaptic Potentials Occurs in the Dendrites and Soma
The transduction of information between neurons in the nervous system is mediated by changes in the membrane po tential of the postsynaptic cell. These membrane depolarizations and hyperpolarizations are integrated or summated and can result in activation or inhibition of the postsynaptic neuron. Alterations in the membrane potential that occur in the postsynaptic neuron initially take place in the dendrites and the soma as a result of the activation of afferent inputs.
Since depolarizations can lead to the excitation and activation of a neuron, they are commonly called excitatory postsynaptic potentials (EPSPs). In contrast, hyperpolar-izations of the membrane prevent the cell from becoming activated and are called inhibitory postsynaptic potentials (IPSPs). These membrane potential changes are caused by the influx or efflux of specific ions (Fig. 3.10).
The rate at which the membrane potential of a postsy-naptic neuron is altered can greatly influence the efficiency of transducing information from one neuron to the next. If the activation of a synapse leads to the influx of positively charged ions, the postsynaptic membrane will depolarize. When the influx of these ions is stopped, the membrane will repolarize back to the resting level. The rate at which it re-polarizes depends on the membrane time constant, t, which is a function of membrane resistance and capacitance and represents the time required for the membrane potential to decay to 37% of its initial peak value (Fig. 3.11).
The decay rate for repolarization is slower for longer time constants because the increase in membrane resistance and/or capacitance results in a slower discharge of the membrane. The slow decay of the repolarization allows additional time for the synapse to be reactivated and depolarize the membrane. A second depolarization of the mem-
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