The 17 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is a replicated candidate gene for schizophrenia and is also protective in inflammation and stress. The protein subunit (17), derived from the gene, assembles with four other like subunits to form the pentameric, functional 17* receptor, which has five agonist-binding sites. The 17* receptor is an important target in drug development for cognitive deficits in schizophrenia. Agonist stimulation results in opening of the channel and entry of mono- and divalent cations, including Ca++, leading presynaptically to neurotransmitter release and postsynaptically to regulation at the post-synaptic density (PSD) and to down-stream changes in gene expression. Structure of CHRNA7, is complex;it is partially duplicated as a chimeric gene (CHRFAM7A). The chimera, CHRFAM7A, is expressed. Recent data suggests that CHRFAM7A acts as a dominant negative regulator of CHRNA7 binding and function. A 2bp deletion in CHRFAM7A is associated with schizophrenia and results in further decreasing CHRNA7 function. Schizophrenic patients have low levels of 17* receptors, as measured by binding of the ligand [125I]-1-bungarotoxin (I-BTX). Most of these patients are heavy cigarette smokers. The mRNA and protein in schizophrenic non-smokers is reduced compared to controls, but in the majority of subjects who smoke, there are normal levels of mRNA and protein. Thus, the low levels of I-BTX binding in schizophrenic patients are not explained by CHRNA7 mRNA or protein expression. We hypothesize that the duplicated gene, CHRFAM7A, acting as a dominant negative regulator, decreases the surface binding and function of 17* receptors. The current proposal will characterize the structure, expression and regulation of the CHRFAM7A gene and investigate its interaction with the full-length gene, CHRNA7.
The prevalence of schizophrenia is approximately 10% in Veterans, much higher than in the general population. Addiction, particularly to nicotine, is higher, ~35% in Veterans compared to 22% in the general population. Smoking and schizophrenia are intimately related since more than 80% of schizophrenics smoke, possibly as a form of self-medication. Nicotinic receptors are involved in both schizophrenia and smoking. The 17* nicotinic acetylcholine receptor, a replicated candidate gene in schizophrenia, is decreased in expression in schizophrenic brain and plays a role in nicotine addiction. A partial duplication of the receptor gene, CHRNA7, regulates its function. This proposal will characterize the partial duplication, CHRFAM7A, at the molecular level and study its expression in schizophrenia. The proposed research will contribute to development of additional 17* receptor-targeted drugs for cognition.
| Sinkus, Melissa L; Graw, Sharon; Freedman, Robert et al. (2015) The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function. Neuropharmacology 96:274-88 |
