Presynaptic terminal

Steps Neurotransmission

Deaminated metabolites a2-Adrenergic receptor

Postsynaptic cell

Postsynaptic cell

Dopamine Receptor Synaptic Cleft

Deaminated metabolites

Adrenergic receptor


O-methylated metabolites Deaminated metabolites

^FHfflRHIflH^Catecholaminergic neurotransmission. A, In dopamine-producing nerve terminals, dopamine is enzymatically synthesized from tyrosine and taken up and stored in vesicles. The fusion of DA-containing vesicles with the terminal membrane results in the release of DA into the synaptic cleft and permits DA to bind to dopamine receptors (D1 and D2) in the postsynaptic cell. The termination of DA neurotransmission occurs when DA is transported back into the presynaptic terminal via a high-affinity mechanism. B, In norepinephrine (NE)-producing nerve terminals, DA is transported into synaptic

Most of the catecholamine released into the synapse (up to 80%) is rapidly removed by uptake into the presynaptic neuron. Once inside the presynaptic neuron, the transmitter enters the synaptic vesicles and is made available for recycling. In peripheral noradrenergic synapses (the sympathetic nervous system), the neuronal uptake process described above is referred to as uptake 1, to distinguish it from a second uptake mechanism, uptake 2, localized in the target cells (smooth muscle, cardiac muscle, and gland cells) (Fig. 3.19B). In contrast with uptake 1, an active transport, uptake 2 is a facilitated diffusion mechanism, which takes up the sympathetic transmitter NE, as well as the circulating hormone EPI, and degrades them enzymat-ically by MAO and COMT localized in the target cells. In the CNS, there is little evidence of an uptake 2 of NE, but vesicles and converted into NE by the enzyme dopamine P-hy-droxylase (DBH). On release into the synaptic cleft, NE can bind to postsynaptic a- or P-adrenergic receptors and presynaptic a2-adrenergic receptors. Uptake of NE into the presynaptic terminal (uptake 1) is responsible for the termination of synaptic transmission. In the presynaptic terminal, NE is repackaged into vesicles or deaminated by mitochondrial MAO. NE can also be transported into the postsynaptic cell by a low-affinity process (uptake 2), in which it is deaminated by MAO and O-methylated by catechol-O-methyltransferase (COMT).

glia serve a comparable role by taking up catecholamines and degrading them enzymatically by glial MAO and COMT. Unlike uptake 2 in the PNS, glial uptake of cate-cholamines has many characteristics of uptake 1.

The catecholamines differ substantially in their interactions with receptors,- DA interacts with DA receptors and NE and EPI interact with adrenergic receptors. Up to five subtypes of DA receptors have been described in the CNS. Of these five, two have been well characterized. Dj receptors are coupled to stimulatory G proteins (Gs), which activate adenylyl cyclase, and D2 receptors are coupled to inhibitory G proteins (G¡), which inhibit adenylyl cyclase. Activation of D2 receptors hyperpolarizes the postsynaptic membrane by increasing potassium conductance. A third subtype of DA receptor postulated to modulate the release of DA is local ized on the cell membrane of the nerve terminal that releases DA,- accordingly, it is called an autoreceptor.

Adrenergic receptors, stimulated by EPI and NE, are located on cells throughout the body, including the CNS and the peripheral target organs of the sympathetic nervous system (see Chapter 6). Adrenergic receptors are classified as either a or P, based on the rank order of potency of catecholamines and related analogs in stimulating each type. The analogs used originally in distinguishing a- from P-adrenergic receptors are NE, EPI, and the two synthetic compounds isoproterenol (ISO) and phenylephrine (PE). Ahlquist, in 1948, designated a as those receptors in which EPI was highest in potency and ISO was least potent (EPI > NE > > ISO). P-Receptors exhibited a different rank order: ISO was most potent and EPI either more potent or equal in potency to NE. Studies with PE further distinguished these two classes of receptors: a-receptors were stimulated by PE, whereas P-receptors were not.

Serotonin. Serotonin or 5-hydroxytryptamine (5-HT) is the transmitter in serotonergic neurons. Chemical transmission in these neurons is similar in several ways to that described for catecholaminergic neurons. Tryptophan hydroxylase, a marker of serotonergic neurons, converts tryptophan to 5-hydroxytryptophan (5-HTP), which is then converted to 5-HT by decarboxylation (Fig. 3.20).

5-Hydroxytryptamine is stored in vesicles and is released by exocytosis upon nerve depolarization. The major mode of removal of released 5-HT is by a high-affinity, sodium-dependent, active uptake mechanism. There are several receptor subtypes for serotonin. The 5-HT-3 receptor contains an ion channel. Activation results in an increase in sodium and potassium ion conductances, leading to EPSPs. The remaining well-characterized receptor subtypes appear to operate through second messenger systems. The 5-HT-1A receptor, for example, uses cAMP. Activation of this receptor results in an increase in K.+ ion conductance, producing IPSPs.

Glutamate and Aspartate. Both glutamate (GLU) and aspartate (ASP) serve as excitatory transmitters of the CNS. These dicarboxylic amino acids are important substrates for transaminations in all cells, but, in certain neurons, they also serve as neurotransmitters—that is, they are sequestered in high concentration in synaptic vesicles, released by exocytosis, stimulate specific receptors in the synapse, and are removed by high-affinity uptake. Since GLU and ASP are readily interconvertible in transamination reactions in cells, including neurons, it has been difficult to distinguish neurons that use glutamate as a transmit-

Serotonergic Transmission

Serotonergic neurotransmission. Serotonin "(5-HT) is synthesized by the hydroxylation of tryptophan to form 5-hydroxytryptophan (5-HTP) and the decarboxylation of 5-HTP to form 5-HT. On release into the synaptic cleft, 5-HT can bind to a variety of serotonergic receptors on the postsynaptic cell. Synaptic transmission is terminated when 5-HT is transported back into the presynaptic terminal for repackaging into vesicles.

Glutamatergic neurotransmission. Glutamate (GLU) is synthesized from a-ketoglutarate by enzymatic amination. Upon release into the synaptic cleft, GLU can bind to a variety of receptors. The removal of GLU is primarily by transport into glial cells, where it is converted into gluta-mine. Glutamine, in turn, is transported from glial cells to the nerve terminal, where it is converted to glutamate by the enzyme glutaminase.

ter from those that use aspartate. This difficulty is further compounded by the fact that GLU and ASP stimulate common receptors. Accordingly, it is customary to refer to both as glutamatergic neurons.

Sources of GLU for neurotransmission are the diet and mitochondrial conversion of a-ketoglutarate derived from the Krebs cycle (Fig. 3.21). Glutamate is stored in vesicles and released by exocytosis, where it activates specific receptors to depolarize the postsynaptic neuron. Two efficient active transport mechanisms remove GLU rapidly from the synapse. Neuronal uptake recycles the transmitter by re-storage in vesicles and re-release. Glial cells (particularly astrocytes) contain a similar, high-affinity, active transport mechanism that ensures the efficient removal of excitatory neurotransmitter molecules from the synapse (see Fig. 3.21). Glia serves to recycle the transmitter by converting it to glutamine, an inactive storage form of GLU containing a second amine group. Glutamine from glia readily enters the neuron, where glutaminase removes the second amine, regenerating GLU for use again as a transmitter.

At least five subtypes of GLU receptors have been described, based on the relative potency of synthetic analogs in stimulating them. Three of these, named for the synthetic analogs that best activate them—kainate, quisqualate, and N-methyl-d-aspartate (NMDA) receptors—are associated with cationic channels in the neuronal membrane. Activation of the kainate and quisqualate receptors produces EPSPs by opening ion channels that increase Na+ and K.+ conductance. Activation of the NMDA receptor increases Ca2+ conductance. This receptor, however, is blocked by Mg2+ when the membrane is in the resting state and becomes unblocked when the membrane is depolarized. Thus, the NMDA receptor can be thought of as both a ligand-gated and a voltage-gated channel. Calcium gating through the NMDA receptor is crucial for the development of specific neuronal connections and for neural processing related to learning and memory. In addition, excess entry of Ca2+ through NMDA receptors during is-chemic disorders of the brain is thought to be responsible for the rapid death of neurons in stroke and hemorrhagic brain disorders (see Clinical Focus Box 3.2).

7-Aminobutyric Acid and Glycine. The inhibitory amino acid transmitters 7-aminobutyric acid (GABA) and glycine (GLY) bind to their respective receptors, causing hyperpolar-

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