This is a request for an ADAMHA Research Scientist Award (RSA). The brain is an information processor that generates behavior. The functional units for information transfer are the ionic channels in the neuronal membrane. This study aims to test the hypothesis that an etiological component underlying neuropsychiatric diseases such as affective disorders and schizophrenia may be a dysfunction of channel proteins. Our immediate goal is to understand how a channel protein works. To elucidate channel protein structure-function relationships a multidisciplinary yet focused approach encompassing techniques of membrane biophysics, molecular biology and protein engineering will be implemented. The strategy requires the primary structure of the protein to apply empirical secondary structure predictors in order to postulate a structural model. It is then followed by the design and synthesis of peptides proposed to be transmembrane functional components of the assembly (i.e. the """"""""pore"""""""" or the """"""""sensor"""""""") and the functional assay of the synthetic channel in lipid bilayers. A salient advantage is that, by chemical synthesis, an amino acid thought to be crucial for function can be substituted. The assay of the """"""""analogue"""""""" will establish is such residue is functionally significant. Concurrently, small perturbations in the structure of the protein will be produced by site directed mutagenesis of the gene followed by the functional assay of the mutant channel in membrane patches of Xenopus oocytes. The synthetic and the recombinant strategies complementing each other should provide an even more powerful path to establish structure-function relationships in channel proteins. This program will be initially focused on the voltage sensitive sodium channel and the nicotinic cholinergic receptor as prototypes of two major and distinct gene families in the brain. The ultimate goal is to blend psychiatry with the biology and chemistry of brain channel proteins as focused on structure-function correlations to gain new insights into the etiology of mental disorders. The direction of my professional growth has been and will continue to be guided by the goal of my research for the past 20 years: To reduce the complexity of the brain form and function to the language of chemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Award (K05)
Project #
5K05MH000778-05
Application #
3075862
Study Section
Research Scientist Development Review Committee (MHK)
Project Start
1989-08-01
Project End
1994-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ferrer-Montiel, A V; Sun, W; Montal, M (1995) Molecular design of the N-methyl-D-aspartate receptor binding site for phencyclidine and dizolcipine. Proc Natl Acad Sci U S A 92:8021-5
Planells-Cases, R; Ferrer-Montiel, A V; Patten, C D et al. (1995) Mutation of conserved negatively charged residues in the S2 and S3 transmembrane segments of a mammalian K+ channel selectively modulates channel gating. Proc Natl Acad Sci U S A 92:9422-6
Montal, M (1995) Design of molecular function: channels of communication. Annu Rev Biophys Biomol Struct 24:31-57
Sun, W; Ferrer-Montiel, A V; Montal, M (1994) Primary structure and functional expression of the AMPA/kainate receptor subunit 2 from human brain. Neuroreport 5:441-4
Oblatt-Montal, M; Reddy, G L; Iwamoto, T et al. (1994) Identification of an ion channel-forming motif in the primary structure of CFTR, the cystic fibrosis chloride channel. Proc Natl Acad Sci U S A 91:1495-9
Collins, C; Duff, C; Duncan, A M et al. (1993) Mapping of the human NMDA receptor subunit (NMDAR1) and the proposed NMDA receptor glutamate-binding subunit (NMDARA1) to chromosomes 9q34.3 and chromosome 8, respectively. Genomics 17:237-9
Planells-Cases, R; Sun, W; Ferrer-Montiel, A V et al. (1993) Molecular cloning, functional expression, and pharmacological characterization of an N-methyl-D-aspartate receptor subunit from human brain. Proc Natl Acad Sci U S A 90:5057-61
Ferrer-Montiel, A V; Montal, M (1993) A negative charge in the M2 transmembrane segment of the neuronal alpha 7 acetylcholine receptor increases permeability to divalent cations. FEBS Lett 324:185-90
Montal, M O; Iwamoto, T; Tomich, J M et al. (1993) Design, synthesis and functional characterization of a pentameric channel protein that mimics the presumed pore structure of the nicotinic cholinergic receptor. FEBS Lett 320:261-6
Schinder, A F; Montal, M (1993) Two distinct modalities of NMDA-receptor inactivation induced by calcium influx in cultured rat hippocampal neurons. FEBS Lett 332:44-8

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