[
    {
        "id": "thesis:8927",
        "collection": "thesis",
        "collection_id": "8927",
        "cite_using_url": "https://resolver.caltech.edu/CaltechTHESIS:05292015-144036736",
        "primary_object_url": {
            "basename": "Christopher_Bruno_Marotta_2015-0522-Thesis.pdf",
            "content": "final",
            "filesize": 14106595,
            "license": "other",
            "mime_type": "application/pdf",
            "url": "/8927/1/Christopher_Bruno_Marotta_2015-0522-Thesis.pdf",
            "version": "v3.0.0"
        },
        "type": "thesis",
        "title": "Structure-Function Studies of Nicotinic Acetylcholine Receptors Using Selective Agonists and Positive Allosteric Modulators",
        "author": [
            {
                "family_name": "Marotta",
                "given_name": "Christopher Bruno",
                "orcid": "0000-0002-3110-0819",
                "clpid": "Marotta-Christopher-Bruno"
            }
        ],
        "thesis_advisor": [
            {
                "family_name": "Dougherty",
                "given_name": "Dennis A.",
                "clpid": "Dougherty-D-A"
            }
        ],
        "thesis_committee": [
            {
                "family_name": "Rees",
                "given_name": "Douglas C.",
                "clpid": "Rees-D-C"
            },
            {
                "family_name": "Barton",
                "given_name": "Jacqueline K.",
                "clpid": "Barton-J-K"
            },
            {
                "family_name": "Miller",
                "given_name": "Thomas F.",
                "clpid": "Miller-T-F"
            },
            {
                "family_name": "Dougherty",
                "given_name": "Dennis A.",
                "clpid": "Dougherty-D-A"
            }
        ],
        "local_group": [
            {
                "literal": "div_chem"
            }
        ],
        "abstract": "<p>This dissertation primarily describes chemical-scale studies of nicotinic acetylcholine receptors (nAChRs) in order to better understand ligand-receptor selectivity and allosteric modulation influences during receptor activation. Electrophysiology coupled with canonical and non-canonical amino acids mutagenesis is used to probe subtle changes in receptor function.</p>\r\n\t\r\n<p>The first half of this dissertation focuses on differential agonist selectivity of \u03b14\u03b22-containing nAChRs. The \u03b14\u03b22 nAChR can assemble in alternative stoichiometries as well as assemble with other accessory subunits. Chapter 2 identifies key structural residues that dictate binding and activation of three stoichiometry-dependent \u03b14\u03b22 receptor ligands: sazetidine-A, cytisine, and NS9283. These do not follow previously suggested hydrogen-bonding patterns of selectivity. Instead, three residues on the complementary subunit strongly influence binding ability of a ligand and receptor activation. Chapter 3 involves isolation of a \u03b15\u03b14\u03b22 receptor-enriched population to test for a potential alternative agonist binding location at the \u03b15 \u03b14 interface. Results strongly suggest that agonist occupation of this site is not necessary for receptor activation and that the \u03b15 subunit only incorporates at the accessory subunit location.</p>\r\n\t\r\n<p>The second half of this dissertation seeks to identify residue interactions with positive allosteric modulators (PAMs) of the \u03b17 nAChR. Chapter 4 focuses on methods development to study loss of potentiation of Type I PAMs, which indicate residues vital to propagation of PAM effects and/or binding. Chapter 5 investigates \u03b17 receptor modulation by a Type II PAM (PNU 120596). These results show that PNU 120596 does not alter the agonist binding site, thus is relegated to influencing only the gating component of activation. From this, we were able to map a potential network of residues from the agonist binding site to the proposed PNU 120596 binding site that are essential for receptor potentiation.</p>",
        "doi": "10.7907/Z9V122Q9",
        "publication_date": "2015",
        "thesis_type": "phd",
        "thesis_year": "2015"
    }
]