Histamine (re)uptake by astrocytes: an experimental and computational study.
Astrocytes participate in the clearance of neurotransmitters by their uptake and subsequent enzymatic degradation. Histamine as a polar and/or protonated molecule must use a carrier to be transported across the cell membrane, although a specific histamine transporter has not been elucidated, yet. In this work we upgraded the kinetic studies of histamine uptake into neonatal rat cultured type 1 astrocytes with quantum chemical calculations of histamine pKa values in conjunction with Langevin dipoles solvation model as the first step toward microscopic simulation of transport. Our results indicate that astrocytes transport histamine by at least two carrier mediated processes, a concentration gradient dependent passive and a sodium-dependent and ATP-driven active transport. We also demonstrated that histamine protonation states depend on the polarity of the environment. In conclusion we suggest that histamine, a polar molecule at physiological pH uses at least two different mechanisms for its uptake into astrocytes -an electrodiffusion and Na(+)-dependent and ouabain sensitive active process. We emphasize relevance of knowledge of histamines protonation states at the rate limiting step of its transport for microscopic simulation that will be possible when structure of histamine transporter is known.
Perdan-Pirkmajer
Katja
K
Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, Si-1001, Ljubljana, Slovenia. katja.perdan@mf.uni-lj.si
Mavri
Janez
J
Krzan
Mojca
M
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006632:Histamine / Q000737:chemistry / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D008956:Models, Chemical; D010042:Ouabain / Q000494:pharmacology; D011522:Protons; D011789:Quantum Theory; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D014867:Water / Q000737:chemistry
D004791:Enzyme Inhibitors; D011522:Protons; D014867:Water; D010042:Ouabain; D006632:Histamine; D000255:Adenosine Triphosphate; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase