Therapeutic Implications of a Selective á 7 Nicotinic Receptor Abnormality in Schizophrenia Stephen I. Deutsch, MD, PhD, 1,2,3 Richard B. Rosse, MD, 1,2 Barbara L. Schwartz, PhD, 1,2 Abraham Weizman, MD, 4 Melissa Chilton, BS, 1 David S. Arnold, MD, 1,3 and John Mastropaolo, PhD 1 1 Department of Veterans Affairs Medical Center, Washington, D.C., U.S.A. 2 Department of Psychiatry, Georgetown University of Medicine, Washington, D.C., U.S.A. 3 Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, U.S.A. 4 Department of Psychiatry, Sackler School of Medicine, Tel Aviv, Israel. Abstract: A convergence of preclinical pharmacology, and human autopsy and genetic data support the existence of re- duced expression and function of the á 7 nicotinic receptor in patients with schizophrenia. The á 7 nicotinic receptor is a member of a family of ligand-gated ion channels. The á 7 nicotinic receptor may play an essential role in auditory sen- sory gating and voluntary smooth pursuit eye movements, two psychophysiological functions that are abnormal in pa- tients with schizophrenia and closely related unaffected biological relatives. Diminished expression or function of the á 7 nicotinic receptor in schizophrenia has stimulated consideration of selective full or partial á 7 nicotinic receptor agonists as possible therapeutic interventions for this disorder. Further, the availability of positive allosteric modula- tors of nicotinic receptors that can improve the efficiency of transduction of the acetylcholine signal and prevent the rapid desensitization of the receptor should encourage these novel treatment approaches (e.g., galantamine). Nicotinic Acetylcholine Receptors: Structural and Functional Considerations Nicotinic acetylcholine receptors (nAChRs) are members of a large family of ligand-gated ion chan- nels, which include receptors for GABA, glycine and serotonin, that mediate “fast” synaptic transmission or signaling events within a millisecond timeframe (1-3). Members of this receptor family are pentameric proteins comprised of five polypeptide subunits, each of which is derived from a common ancestral protein. Although at least 16 genetically distinct, albeit related, types of nicotinic acetylcho- line receptor subunits have been cloned from several species (referred to as á1-á9, â1-â4, ã, ä, å), they all share a common motif with a large extracellular N- terminal hydrophilic domain, three trans- membranous hydrophobic domains (M1-M3), an intracellular loop, and a final C-terminal transmembranous segment (M4). The extracellular domains have one or more glycosylation sites, and the intracellular loop possesses consensus sequences of amino acids that serve as substrates for enzymatic phosphorylation. The M2 transmembranous do- mains from each of the five polypeptide receptor subunits align themselves in a manner to surround a potential pore or channel that traverses the lipid bilayer. The transient assumption of the open configura- tion of this channel, or activation of the receptor, al- lowing cationic conductance, is more likely to occur as a result of the binding of acetylcholine. Further, allosteric modulatory sites distinct from the agonist recognition site for acetylcholine exist on the recep- tor; ligands binding to these sites influence the likeli- hood that acetylcholine will be effective in promoting the transition from the closed configura- tion of the channel to an open one (1-4). Subsequent to the binding of acetylcholine, the channels will also transition into a desensitized or refractory state, which neither permits cationic conductance nor is sensitive to activation by acetylcholine. Allosteric modulatory ligands may also influence the kinetics of transitions into the desensitized state and the du- Isr J Psychiatry Relat Sci Vol 42 No. 1 (2005) 33–44 Address for Correspondence: Stephen I. Deutsch, MD, PhD, Director, Mental Health Service Line, VISN5, Department of Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, D.C. 20422, U.S.A. E-mail: Stephen.Deutsch@med.va.gov