Toshio Narahashi, PhD Alfred N. Richards Professor of Pharmacology John Evans Professor of Pharmacology Molecular Pharmacology and Biological Chemistry Pharmacology of Neuroreceptors and Ion Channels Curricula: Neurobiology Pharmacology and Toxicology E-mail:   narahashi@northwestern.edu

Neuroreceptors and ion channels in the nervous system are the important target sites for a variety of therapeutic drugs and toxicants. We have been studying the mechanisms by which these chemicals modulate the function of various ion channels thereby causing therapeutic or toxic effects. The pharmacology and toxicology of ion channels have become one of the most important areas in biomedical sciences. Our recent study utilizes patch clamp techniques as applied to various cultured or dissociated mammalian neurons. These techniques allow us to measure the activity of any types of ion channels with a high degree of precision, and when combined with molecular biology techniques, the molecular structure of ion channels that are responsible for drug modulation can be determined.

A few examples of our most recent studies: Ethanol at low concentrations stimulates neuronal nicotinic acetylcholine receptors in a subunit-dependent manner thereby causing various behavioral effects via a cascade of multisynaptic events. Our long-standing study of the pyrethroid insecticides has clearly established that the sodium channel is the major target site. The selective toxicity of several insecticides could be explained by differential sensitivities of mammalian vs insect target receptors/channels. The nootropic drug (cognitive enhancer) nefiracetam stimulates both neuronal nicotinic acetylcholine receptors and NMDA receptors at very low concentrations thereby improving memory and learning. Inhalational general anesthetics such as isoflurane and sevoflurane inhibit the nicotinic acetylcholine receptos and glutamate receptors, and stimulate GABA receptors. These actions lead the patients to general anesthesia.

The results of these studies pave the way to the development of new therapeutic drugs and new treatment methods for intoxication.

Publications:

Mori, T., X. Zhao, Y. Zuo, G.L. Aistrup, K. Nishikawa, W. Marszalec, J.Z. Yeh and T. Narahashi (2001). Modulation of neuronal nicotinic acetylcholine receptors by halothane in rat cortical neurons. Mol. Pharmacol. 59, 732-743.

Zuo, Y., J.Z. Yeh and T. Narahashi (2003). Dual action of n-butanol on neuronal nicotinic a4b2 acetylcholine receptors. J. Pharmacol. Exp. Ther. 304, 1143-1152.

Moriguchi, S., W. Marszalec, X. Zhao, J.Z. Yeh and T. Narahashi (2003). Potentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neurons. J. Pharmacol. Exp. Ther.  307, 160-167.

Zhao, X., V.L. Salgado, J.Z. Yeh and T. Narahashi (2003). Differential actions of fipronil and dieldrin insecticides on GABA-gated chloride channels in cockroach neurons. J. Pharmacol. Exp. Ther. 306, 914-924.