Pharmacological Transport

Rostene, W., Boja, J.W., Scherman, D., Carroll, F.I., and Kuhar, M.J., Dopamine transport pharmacological distinction between the synaptic membrane and vesicular transporter in rat striatum, Eur. J. Pharmacol., 281, 175, 1992. 

Fleckenstein, A. E., Gibb, J. W. and Hanson, G. R. Differential effects of stimulants on monoaminergic transporters pharmacological consequences and implications for neurotoxicity. Eur. J. Pharmacol. 406 1-13,2000. 

Absorbed ptemutagen activation deactivation transport Pharmacologic dose mg/kg... 

Joyce JN, Murray AM (1993) Dr and D2-like dopamine receptors in human brain. In Niznik HB (Ed), Dopamine receptors and transporters. Pharmacology, structure and function, pp. 345-381. Marcel Dekker, New York. 

Gainetdinov RR, Sotnikova TD, Caron MG. 2002. Monoamine transporter pharmacology and mutant mice. Trends Pharmacol. Sci. 23 367-73... 

Jarvie, K.R. Tiberi, M. Caron, M.G. (1994) Dopamine Dla and Dlb receptors. In Niznik, H.B. (Ed) Dopamine receptors and transporters-Pharmacology, Structure and Function. Marcel Dekker Inc, New York, 133-150. 

Tan J, Zelenaia O, Correale D, Rothstein JD, Robinson MB (1999) Expression of the GLT-1 subtype of Na+-dependent glutamate transporter pharmacological characterization and lack of regulation by protein kinase... 

Care should be exercised when attempting to interpret in vivo pharmacological data in terms of specific chemical—biological interactions for a series of asymmetric compounds, particularly when this interaction is the only parameter considered in the analysis (10). It is important to recognize that the observed difference in activity between optical antipodes is not simply a result of the association of the compound with an enzyme or receptor target. Enantiomers differ in absorption rates across membranes, especially where active transport mechanisms are involved (11). They bind with different affinities to plasma proteins (12) and undergo alternative metaboHc and detoxification processes (13). This ultimately leads to one enantiomer being more available to produce a therapeutic effect. 

The ABC-transporter superfamily represents a large group of transmembrane proteins. Members of this family are mainly involved in ATP-dependent transport processes across cellular membranes. These proteins are of special interest from a pharmacological point of... 

Aminoimidazole-4-carboxamide ribonucleoside (also known as AICA riboside or AICAR). An adenosine analogue that is taken up into cells by adenosine transporters and converted by adenosine kinase to the monophosphorylated nucleotide form, ZMP. ZMP is an analogue of AMP that activates the AMP-activated protein kinase (AMPK), for which acadesine or AICAR can be used as a pharmacological activator. 

The first pharmacological agent shown to activate AMPK was 5-aminoimidazole-4-carboxamide (AICA) riboside, also known as acadesine. This adenosine analogue is taken up into cells by adenosine transporters and phosphoiylated by adenosine kinase to the mono-phosphorylated form, AICA ribotide or ZMP. ZMP accumulates inside cells to higher concentrations than the concentration of AICA riboside present in the medium, and it mimics both effects of AMP on AMPK system (allosteric activation and inhibition of... 

The most common treatment of ADHD is pharmacological. Psychostimulant diugs such as methylpheni-date and amphetamine or atomoxetin, an inhibitor of the noradrenaline transporter can be prescribed. These agents elicit the non-exocytotic release of... 

Unfortunately, the pharmacology of chloride channels is poorly developed. Specific and highly useful inhibitors or modulators (e.g. strychnine, picrotoxin, diazepams) are only available for ligand-gated chloride channels (but these are covered in a different chapter). There are several chloride channel inhibitors such as the stilbene-disulfonates DIDS and SITS, 9-antracene-carboxylic acid (9-AC), arylaminobenzoates such as DPC and NPPB, niflumic acids and derivates, sulfony-lureas, and zinc and cadmium. All of these inhibitors, however, are not veiy specific. Several of these inhibitors (e.g. DIDS) inhibit many chloride channels only partially even at millimolar concentrations and have effects on other types of transport proteins. 

The localization of transporter molecules on the cell surface is dynamic rather than constitutive, such that transport capacity may be adapted to neuronal activity. Obviously, the mechanisms regulating uptake are of principal importance in pharmacology just as pharmacological transport inhibitors can regulate the density of transporters. 

Kanai Y, Hediger MA (2004) The glutamate/neutral amino acid transporter family SLC1 molecular, physiological and pharmacological aspects. Pfliigers Arch 447 469-479... 

Sitte HH, Freissmuth M (eds) (2006) Neurotransmitter transporters. Handbook of Experimental Pharmacology. Springer-verlag, Berlin Heidelberg, 175... 

Most pharmacological strategies for the treatment of protein transport diseases aim to rescue mutant proteins... 

Neither chemical nor pharmacological chaperones lead to wild-type expression levels of the mutant proteins at the cell surface. Alternative or additional strategies are needed to improve the intracellular transport of the mutant proteins. In the future, dtugs may also be developed that influence those components of the quality control system that are involed in the retention of misfolded proteins. 

The pharmacology of amphetamine is considerably more complex. It does not only block monoamine reuptake, but also directly inhibits the vesicular monoamine transporter, causing an increase in cytosolic but not vesicular dopamine concentration. This may lead to reverse transport of the amines via the membrane-bound transporters. Further mechanisms of amphetamine action are direct MAO inhibition and indirect release of both dopamine and serotonin in the striatum. 

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