Catecholamines transporters

Until recently, d-fenfiuramine was used to control appetite, in preference to d-amphetamine, because it has a lower affinity for the catecholamine transporter and so its uptake into noradrenergic and dopaminergic neurons is much less than that of amphetamine. This is thought to explain why, at anorectic doses, this compound lacks the psychotropic effects and dependence-liability that are real problems with if-amphetamine. Unfortunately, despite this therapeutic advantage, this compound has had to be withdrawn from the clinic because of worries that it might cause primary pulmonary hypertension, valvular heart disease and even long-term neuropathy. 

Some less obvious phenomena of catecholamine transport and biosynthesis further illustrate the complexities of deciphering how efferents from midbrain dopamine neurons contribute to sleep-wake regulation. The plasma membrane norepinephrine transporter (NET), which is responsible for the uptake of extracellular noradrenaline, can also readily transport dopamine, and does so in vivo. This... 

BreidertT, Spitzenberger F, Grunde-mann D, Schomig E. Catecholamine transport by the organic cation transporter type 1 (OCT1). Br J Pharmacol 1998 ... 

Grundemann D, Schechinger B, Rap-pold GA, Schomig E. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nature Neurosci 1998 1(5) 349 351. 

Buck, K. J. and Amara, S. G. (1995) Structural domains of catecholamine transporter chimeras involved in selective inhibition by antidepressants and psychomotor stimulants. Mol. Pharmacol. 48,1030-1037. 

Weaver JA, Deupree JD (1982) Conditions required for reserpine binding to the catecholamine transporter on chromaffin granule ghosts. Eur J Pharmacol 80 437 438. 

Lorang D, Amara SG, Simerly RB (1994) Cell-type-specific expression of catecholamine transporters in the rat brain. J Neurosci 74 4903-4914. 

V-Na+ CH (inactivated form) blocker (catecholamine transport inhibition) [central nervous system (CNS) stimulant, local anaesthetic, mydriatic, narcotic]... 

Because guanadrel is actively transported to its site of action, drugs that block or compete for the catecholamine transporter on the presynaptic membrane will inhibit the effect of guanadrel. Such drugs include the tricyclic antidepressants, cocaine, chlorpromazine, ephedrine, phenylpropanolamine, and amphetamine. 

Pharmacological agents also have been used to probe the mechanism by which DA transport occurs. It has been shown, in a simplified preparation, that the kinetics of the catecholamine transporters can be desalbed Figure 8A [62,63]. This scheme describes transport as a series of steps the competition between binding and dissociation of the substrate to the transporter on the extracellular side, a same competition on the cytoplasmic side, and an equilibrium between the unoccupied transporter facing either side. 

Johnson RG, Carty SE, Scarpa A. Coupling of H gradients to catecholamine transport in chromaffin granules. Ann N Y Acad Sci 1985 456 254. 

Boronic adds with linked ammonium ions have been used by Takeuchi to aid saccharide extraction. Using boronic adds in combination with crown ethers. Smith has developed a sodium-saccharide co-transporter 227 and facilitated catecholamine transporters 228, 229 and 230. Smith has used microporous polypropylene impregnated with a boronic acid in 2-nitrophenyl octyl ether as a supported liquid membrane for the separation of fructose from fermentation broths. ... 

Both R- and 5-enantiomers are analgesic, anesthetic, and sympathomimetic agents differing however in potency and toxicity. 5-ketamine shows greater affinity to opioid receptor and more strongly inhibits catecholamine transport than / -ketamine [35],... 

Together with dopamine, adrenaline and noradrenaline belong to the endogenous catecholamines that are synthesized from the precursor amino acid tyrosine (Fig. 1). In the first biosynthetic step, tyrosine hydroxylase generates l-DOPA which is further converted to dopamine by the aromatic L-amino acid decarboxylase ( Dopa decarboxylase). Dopamine is transported from the cytosol into synaptic vesicles by a vesicular monoamine transporter. In sympathetic nerves, vesicular dopamine (3-hydroxylase generates the neurotransmitter noradrenaline. In chromaffin cells of the adrenal medulla, approximately 80% of the noradrenaline is further converted into adrenaline by the enzyme phenylethanolamine-A-methyltransferase. 

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

The general picture of muscle contraction in the heart resembles that of skeletal muscle. Cardiac muscle, like skeletal muscle, is striated and uses the actin-myosin-tropomyosin-troponin system described above. Unlike skeletal muscle, cardiac muscle exhibits intrinsic rhyth-micity, and individual myocytes communicate with each other because of its syncytial nature. The T tubular system is more developed in cardiac muscle, whereas the sarcoplasmic reticulum is less extensive and consequently the intracellular supply of Ca for contraction is less. Cardiac muscle thus relies on extracellular Ca for contraction if isolated cardiac muscle is deprived of Ca, it ceases to beat within approximately 1 minute, whereas skeletal muscle can continue to contract without an extraceUular source of Ca +. Cyclic AMP plays a more prominent role in cardiac than in skeletal muscle. It modulates intracellular levels of Ca through the activation of protein kinases these enzymes phosphorylate various transport proteins in the sarcolemma and sarcoplasmic reticulum and also in the troponin-tropomyosin regulatory complex, affecting intracellular levels of Ca or responses to it. There is a rough correlation between the phosphorylation of Tpl and the increased contraction of cardiac muscle induced by catecholamines. This may account for the inotropic effects (increased contractility) of P-adrenergic compounds on the heart. Some differences among skeletal, cardiac, and smooth muscle are summarized in... 

The pathway for synthesis of the catecholamines dopamine, noradrenaline and adrenaline, illustrated in Fig. 8.5, was first proposed by Hermann Blaschko in 1939 but was not confirmed until 30 years later. The amino acid /-tyrosine is the primary substrate for this pathway and its hydroxylation, by tyrosine hydroxylase (TH), to /-dihydroxyphenylalanine (/-DOPA) is followed by decarboxylation to form dopamine. These two steps take place in the cytoplasm of catecholaminereleasing neurons. Dopamine is then transported into the storage vesicles where the vesicle-bound enzyme, dopamine-p-hydroxylase (DpH), converts it to noradrenaline (see also Fig. 8.4). It is possible that /-phenylalanine can act as an alternative substrate for the pathway, being converted first to m-tyrosine and then to /-DOPA. TH can bring about both these reactions but the extent to which this happens in vivo is uncertain. In all catecholamine-releasing neurons, transmitter synthesis in the terminals greatly exceeds that in the cell bodies or axons and so it can be inferred... 

As with other monoamines, the actions of 5-HT are terminated by its reuptake from the synapse by another member of the family of Na+/CU-dependent transporters. The 5-HT transporter has many features in common with its catecholamine equivalent (described fully in Chapter 8 see Fig. 8.7), including its presumed 12 transmembrane-spanning domains. However, the cloned 5-HT transporter has a for 5-HT of about 450 nM whereas its K for both noradrenaline and dopamine is some ten thousand-fold greater (Povlock and Amara 1997) which means that it is relatively selective for uptake... 

Mechanism of Action Lithium s pharmacologic mechanism of action is not well understood and probably involves multiple effects. Possibilities include altered ion transport, increased intraneuronal catecholamine metabolism, neuroprotection or increased brain-derived neurotrophic factor, inhibition of second messenger systems, and reprogramming of gene expression.29... 

Amine hormones include the thyroid hormones and the catecholamines. The thyroid hormones tend to be biologically similar to the steroid hormones. They are mainly insoluble in the blood and are transported predominantly (>99%) bound to proteins. As such, these hormones have longer half-lives (triiodothyronine, t3, = 24 h thyroxine, T4, = 7 days). Furthermore, thyroid hormones cross cell membranes to bind with intracellular receptors and may be administered orally (e.g., synthryoid). In contrast to steroid hormones, however, thyroid hormones have the unique property of being stored extra-cellularly in the thyroid gland as part of the thyroglobulin molecule. 

The catecholamines are biologically similar to protein/peptide hormones. These hormones are soluble in the blood and are transported in an unbound form. Therefore, the catecholamines have a relatively short half-life. Because these hormones do not cross cell membranes, they bind to receptors on the membrane surface. Finally, the catecholamines are stored intracellu-larly in secretory granules for future use. 

Large, non-lipid-soluble molecules may cross the capillary wall by transcytosis. This mechanism involves the transport of vesicles from one side of the capillary wall to the other. Many hormones, including the catecholamines and those derived from proteins, exit the capillaries and enter their target tissues by way of transcytosis. 

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