Inhibition mechanism of the nicotinic acetylcholine receptor α3β4 tacrine / Mecanismos de inibição do receptor nicotínico de acetilcolina α3β4 pela tacrina

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Neuronal nicotinic acetylcholine (cholinergic) receptors (nAChRs) are integral membrane proteins and belong to the family of ligand-gated cation channels composed by α and β subunits. These receptors play a key role in the signal transmission between neurons in the central and peripheral nervous system. The α3β4 subtype, for example, is the most expressed neuronal nAChR in autonomic ganglia; α3-containing nAChRs are present at particularly high density in the superior cervical ganglia, pineal, and adrenal glands. They are also present in the substancia nigra, striatum, hippocampus, locus ceruleus, habenulo-interpeduncular tract and cerebellum. The nAChRs are inhibited by a variety of chemical substances, including natural toxins, local anesthetics, abused drugs (e.g., cocaine) and clinically important compounds (e.g., tranquilizers). The mechanism of inhibition of these receptors has been intensively investigated. In this study, we investigated the mechanism by which tacrine (9-1,2,3,4-tetahydroaminoacridine), an agent used clinically to treat Alzheimers disease, inhibits the recombinant rat α3β4 nAChR expressed in KXα3β4R2 cells, using a rapid chemical kinetic technique. The nicotine dissociation constant for the site controlling receptor activation, Kd, is 23 µM and the channel-opening equilibrium constant, Φ-1, is 4. Tacrine inhibits the receptor competitively, with a KI of 0.77 µM.

ASSUNTO(S)

neuronal nicotinic acetylcholine receptors cholinergic receptors tacrine receptores colinérgicos biophysic tacrina receptores nicotínicos de acetilcolina neuronais neurofisiologia rapid chemical kinetic technique biofísica técnica de cinética química rápida

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