As noted in Chapters 1, 4, and 5, several large families of trans-port proteins have been identified. The most important of these are the ABC (ATP-binding cassette) and SLC (solute carrier) trans-porter families. As indicated by the name, the ABC carriers use ATP for transport. The SLC proteins are cotransporters and, in most cases, use the movement of sodium down its concentration gradient as the energy source. Under some circumstances, they also transport transmitters in the reverse direction in a sodium-independent fashion. NET, SLC6A2, the norepinephrine transporter, is a member of the SLC family, as are similar transporters responsible for the reuptake of dopamine (DAT, SLC6A3) and 5-HT (serotonin, SERT, SLC6A4) into the neurons that release these transmit-ters. These transport proteins are found in peripheral tissues and in the CNS wherever neurons using these transmitters are located. NET is important in the peripheral actions of cocaine and the amphetamines. In the CNS, NET and SERT are important targets of several antidepressant drug classes (see Chapter 30). The most important inhibitory transmitter in the CNS, γ-aminobutyric acid (GABA), is the substrate for at least three SLC transporters: GAT1, GAT2, and GAT3. GAT1 is the target of an antiseizure medication (see Chapter 24). Other SLC proteins transport glutamate, the major excitatory CNS transmitter.
+VMAT+TyrosineAxon AMPsHetero-receptorHNE ATP, P TyrA DopamineDopaMetyrosineNorepinephrineautoreceptorTyrosinehydroxylaseNE, ATP, P NETNaV
FIGURE 6–4 Schematic diagram of a generalized noradrenergic junction (not to scale). Tyrosine is transported into the noradrenergic nerve ending or varicosity by a sodium-dependent carrier (A). Tyrosine is converted to dopamine (see Figure 6–5 for details), and transported into the vesicle by the vesicular monoamine transporter (VMAT), which can be blocked by reserpine and tetrabenazine. The same carrier transports norepinephrine (NE) and several related amines into these vesicles. Dopamine is converted to NE in the vesicle by dopamine-β-hydroxylase. Physiologic release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine, cotransmitters, and dopamine-β-hydroxylase. Release can be blocked by drugs such as guanethidine and bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter (NET), which can be blocked by cocaine and certain antidepressants, or into postjunctional or perijunctional cells. Regulatory receptors are present on the presynaptic terminal. SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins.
Bretylium, guanethidine
Cocaine, tricyclic antidepressants
Norepinephrine and epinephrine can be metabolized by several an estimate of catecholamine turnover can be obtained from meaenzymes, as shown in Figure 6–6. Because of the high activity of surement of total metabolites (sometimes referred to as “VMA and monoamine oxidase in the mitochondria of the nerve terminal, metanephrines”) in a 24-hour urine sample. However, metabolism there is significant turnover of norepinephrine even in the resting is not the primary mechanism for termination of action of nor-terminal. Since the metabolic products are excreted in the urine, epinephrine physiologically released from noradrenergic nerves.
CHAPTER 6 Introduction to Autonomic Pharmacology