Rab3--^o synaptobrevin-fl synaptotagmin voltage-sensitive Ca2+ channel postsynaptic receptor-gated ion channel id
SYNAPTIC VESICLES excitatory transmitter (O) inhibitory transmitter (5)
FIGURE 6-2 Steps involved in excitatory and inhibitory neurotransmission. 1. The nerve action potential (AP) consists of a transient self-propagated reversal of charge on the axonal membrane. (The internal potential E. goes from a negative value, through zero potential, to a slightly positive value primarily through increases in Na+ permeability and then returns to resting values by an increase in K+ permeability.) When the AP arrives at the presynaptic terminal, it initiates release of the excitatory or inhibitory transmitter. Depolarization at the nerve ending and entry of Ca2+ initiate docking and then fusion of the synaptic vesicle with the membrane of the nerve ending. Docked and fused vesicles are shown. 2. Combination of the excitatory transmitter with postsynaptic receptors produces a localized depolarization, the excitatory postsynaptic potential (EPSP), through an increase in permeability to cations, most notably Na+. The inhibitory transmitter causes a selective increase in permeability to K+ or Cl-, resulting in a localized hyperpolarization, the inhibitory postsynaptic potential (IPSP). 3. The EPSP initiates a conducted AP in the postsynaptic neuron; this can be prevented, however, by the hyperpolarization induced by a concurrent IPSP. Transmitter action is terminated by enzymatic destruction, by reuptake into the presynaptic terminal or adjacent glial cells, or by diffusion.
vesicles. Peptide neurotransmitters (or precursor peptides) are found in large dense-core vesicles that are transported down the axon from their site of synthesis in the cell body. The arrival of an AP and depolarization of the axonal terminal membrane causes the synchronous release of several hundred quanta of neurotransmitter; a critical step in most but not all nerve endings is the influx of Ca2+, which enters the axonal cytoplasm and promotes fusion between the axo-plasmic membrane and those vesicles in close proximity to it. The contents of the vesicles, including enzymes, other proteins, and cotransmitters (e.g., ATP, NPY) then are discharged to the exterior by exocytosis (see Figure 6-2).
Receptors on soma, dendrites, and axons of neurons respond to neurotransmitters or modulators released from the same neuron or from adjacent neurons or cells. Soma—dendritic receptors are located on or near the cell body and dendrites; when activated, they primarily modify functions of the soma-dendritic region such as protein synthesis and generation of action potentials. Presynaptic receptors are located on axon terminals or varicosities; when activated, they modify functions such as synthesis and release of transmitters. Two main classes of presynaptic receptors have been identified on most neurons, including sympathetic and parasympathetic terminals. Heterore-ceptors are presynaptic receptors that respond to neurotransmitters, neuromodulators, or neurohormones released from adjacent neurons or cells. For example, NE can influence the release of ACh from parasympathetic neurons by acting on a2A, a2B, and a2c receptors, whereas ACh can influence the release of NE from sympathetic neurons by acting on M2 and M4 receptors (see below). The other class of presynaptic receptors are autoreceptors, located on axon terminals of a neuron and activated by the neuron's own transmitter to modify subsequent transmitter synthesis and release. For example, NE may interact with a2A and a2C receptors to inhibit neurally-released NE. Similarly, ACh may interact with M2 and M4 receptors to inhibit neurally-released ACh. Adenosine, dopamine (DA), glutamate, g-aminobutyric acid (GABA), prostaglandins, and enkephalins influence neurally-mediated release of neurotransmitters, in part by altering the function of prejunctional ion channels.
2. Combination of the transmitter with postjunctional receptors and production of the postjunctional potential. The released transmitter diffuses across the synaptic or junctional cleft and combines with specialized receptors on the postjunctional membrane; this often results in a localized increase in the ionic permeability, or conductance, of the membrane. With certain exceptions (noted below), one of three types of permeability change can occur: (a) a generalized increase in the permeability to cations (notably Na+ but occasionally Ca2+), resulting in a localized depolarization of the membrane, i.e., an excitatory postsynaptic potential (EPSP); (b) a selective increase in permeability to anions, usually Cl-, resulting in stabilization or hyperpolarization of the membrane (an inhibitory postsynaptic potential or IPSP); or (c) an increased permeability to K+ (the K+ gradient is directed outward; thus, hyperpolarization results, i.e., an IPSP).
Electrical potential changes associated with the EPSP and IPSP generally result from passive fluxes of ions down concentration gradients. The changes in channel permeability that cause these potential changes are specifically regulated by the specialized postjunctional neurotransmitter receptors (see Chapter 12 and below). In the presence of an appropriate neurotransmitter, the channel opens rapidly to a high-conductance state, remains open for about a millisecond, and then closes. A short pulse of current is observed as a result of the channel's opening and closing. The summation of these microscopic events gives rise to the EPSP. High-conductance ligand-gated ion channels usually permit passage of Na+ or Cl-; K+ and Ca2+ are involved less frequently. The preceding ligand-gated channels belong to a large superfamily of ionotropic receptor proteins that includes the nicotinic, glutamate, serotonin (5-HT) and P2X receptors, which conduct primarily Na+, cause depolarization, and are excitatory, and GABA and glycine receptors, which conduct Cl-, cause hyperpolarization, and are inhibitory. Neurotransmitters also can modulate the permeability of K+ and Ca2+ channels indirectly, often via receptor-G protein interactions (see Chapter 1). Other receptors for neurotransmitters act by influencing the synthesis of intracellular second messengers (e.g., cyclic AMP, cyclic GMP, IP3) and do not necessarily cause a change in membrane potential.
3. Initiation of postjunctional activity. If an EPSP exceeds a certain threshold value, it initiates an action potential in the postsynaptic membrane by activating voltage-sensitive channels in the immediate vicinity. In certain smooth muscle types in which propagated impulses are minimal, an EPSP may increase the rate of spontaneous depolarization, cause Ca2+ release, and enhance muscle tone; in gland cells, the EPSP initiates secretion through Ca2+ mobilization. An IPSP, which occurs in neurons and smooth muscle but not in skeletal muscle, will tend to oppose excitatory potentials simultaneously initiated by other neuronal sources. The ultimate response depends on the summation of all the potentials.
4. Destruction or dissipation of the transmitter and termination of action. To sustain high frequency transmission and regulation of function, the synaptic dwell-time of the primary neurotransmitter must be relatively short. At cholinergic synapses involved in rapid neurotransmission, high and localized concentrations of acetylcholinesterase (AChE) are localized to hydrolyze ACh. When AChE is inhibited, removal of the transmitter occurs principally by diffusion, and the effects of ACh are potentiated and prolonged (see Chapter 8).
Termination of the actions of catecholamines occurs by a combination of simple diffusion and reuptake by the axonal terminals of the released transmitter by the SLC6 family of transporters using energy stored in the transmembrane Na+ gradient (see Tables 2-2 and 6-5). Termination of the actions of 5-HT and GABA and other amino acid transmitters also results from their transport into neurons and surrounding glia by SLC1 and SLC6 family members. Peptide neurotransmitters are hydrolyzed by various peptidases and dissipated by diffusion; specific uptake mechanisms have not been demonstrated for these substances.
5. Nonelectrogenicfunctions. During the resting state, there is a continual slow release of isolated quanta of the transmitter that produces electrical responses at the postjunctional membrane [miniature end-plate potentials (mepps)] that are associated with the maintenance of physiological responsiveness of the effector organ. A low level of spontaneous activity within the motor units of skeletal muscle is particularly important because skeletal muscle lacks inherent tone. The activity and turnover of enzymes involved in the synthesis and inactivation of neu-rotransmitters, the density of presynaptic and postsynaptic receptors, and other characteristics of synapses probably are controlled by trophic actions of neurotransmitters or other trophic factors released by the neuron or the target cells.
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