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Acta Physiologica 2009; Volume 197, Supplement 675
Joint meeting of The Slovenian Physiological Society, The Austrian Physiological Society and The Federation of European Physiological Societies
11/12/2009-11/15/2009
Ljubljana, Slovenia
ASTROCYTES AS A SITE FOR HISTAMINE INACTIVATION
Abstract number: L76
Krzan1 Mojca, Perdan-Pirkmajer1 Katja, Osredkar1 David, Mavri2 Janez
1Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana
2National Chemical Institute, Ljubljana, Slovenia
Synthesis of histamine in histaminergic neurons is catalyzed by histidine decarboxylase. Later on, synthesised histamine is taken up into synaptic vesicles by the vesicular monoamine transporter 2 and released into the synaptic cleft upon depolarization stimuli. The released neurotransmitter histamine is metabolised by the enzyme histamine-N-methyltransferase (HNMT) producing Nt-methylhistamine. In order to be enzymatically degraded or recycled, histamine must be transported either into the presynaptic neuron or into surrounding glial cells. Unlike with other neurotransmitters, the mechanisms by which histamine content is regulated within the brain remain unresolved.
Histamine is a double protonated molecule with corresponding pKa values of 5,8 and 9,4 Therefore, at physiological pH histamine exists as an equilibrium mixture of tautomeric cations, monocation making 96% and dication only 3% and the rest is nonprotonated histamine. As a protonated molecule histamine most probably use a carrier protein in order to cross the cell membrane. Moreover, the protonation states of histamine most probably change during the transport process because of different dielectric properties at different sites of the transport protein. As a preliminary step to molecular simulation of the transport process we ab initio calculated histamine pKa values in conjunction with a microscopic salvation model. We found that histamine can be transported into cultured astrocytes by two processes, active transport which is Na+-but not Cl--dependent and bidirectional with Michaelis constant (Km) of 3.5 ± 0.8 (M and a maximal rate (Vmax) of 7.9 ± 0.3 pmol/mg protein/min. Aside from this cultured glial cells take up histamine also by electrodiffusion, which is not neither temperature nor Na+-dependent and ouabain-sensitive. This step, which shows some characteristics of uptake2, might occur by the aid of one of organic cation transporters or plasma membrane monoamine transporters. Taken up histamine can be metabolized in astrocytes due to expression of HNMT within.
Taken together astrocytes can represent the major inactivation site for histamine, but some facts remain to be unresolved like the existence of specific histamine transporter and the possible release of histamine and/or its metabolites from astrocytes.
To cite this abstract, please use the following information:
Acta Physiologica 2009; Volume 197, Supplement 675 :L76