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You searched for +publisher:"Purdue University" +contributor:("Gregory H Hockerman"). Showing records 1 – 2 of 2 total matches.

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Purdue University

1. Brust Fernandes, Tarsis. FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS.

Degree: PhD, Medicinal Chemistry and Molecular Pharmacology, 2015, Purdue University

G protein-coupled receptors (GPCRs) are drug targets that often activate multiple signaling pathways. The multiple GPCR responses provide opportunities for biased or functionally selective ligands to preferentially modulate one signaling pathway over another. Studies with several GPCRs have suggested that selective activation of signaling pathways downstream of a GPCR may lead to safer and more effective drug therapies. The dopamine D2 receptor is the main target in therapies for Parkinson’s disease and schizophrenia. First and second generation antipsychotic drugs antagonize dopamine D2 receptor. Notably, both these classes of drugs may cause side effects associated with D2 receptor antagonism (e.g. hyperprolactemia and extrapyramidal symptoms). The novel, “third generation” antipsychotic drug, aripiprazole is also used to treat schizophrenia, with the remarkable advantage that its tendency to cause extrapyramidal symptoms is minimal. In this work we studied the molecular pharmacology of aripiprazole and showed that the compound displays ligand bias for modulation of G proteins, being a partial agonist for Gαi/o and a robust antagonist for Gβγ signaling. We have also examined the activation of immediate effectors of the dopamine D2 receptor (i.e. Gαi/o, Gβγ, β-arrestin recruitment) and more complex signaling pathways (i.e., extracellular signal-regulated kinase phosphorylation, heterologous sensitization, and dynamic mass redistribution) in response to a series of D2 receptor ligands. The most commonly used methods to measure ligand bias were employed and compared. Functional selectivity analyses were also employed as tools to explore the relative contribution of immediate dopamine D2 receptor effectors for the activation of more complex signaling pathways. We have further identified novel classes of AC1 inhibitors through both chemical library screening and structure-activity relationship studies. The effects of our best inhibitor (W001) on acute and chronic signaling through the μ-opioid receptor were also examined, revealing an alternative method to induce functional selectivity (i.e. by targeting signaling components that are downstream of GPCRs). Lastly, we showed that W001, which is the most potent selective small molecule AC1 inhibitor described to date, has analgesic properties in a mouse model of inflammatory pain. Advisors/Committee Members: Val J Watts, Jean-Christophe Rochet, Gregory H Hockerman, Donald F Ready.

Subjects/Keywords: adenylyl cyclase; beta-arrestin; biased signaling; functional selectivity; GPCR; G protein

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Brust Fernandes, T. (2015). FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS. (Doctoral Dissertation). Purdue University. Retrieved from https://docs.lib.purdue.edu/open_access_dissertations/1448

Chicago Manual of Style (16th Edition):

Brust Fernandes, Tarsis. “FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS.” 2015. Doctoral Dissertation, Purdue University. Accessed December 15, 2019. https://docs.lib.purdue.edu/open_access_dissertations/1448.

MLA Handbook (7th Edition):

Brust Fernandes, Tarsis. “FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS.” 2015. Web. 15 Dec 2019.

Vancouver:

Brust Fernandes T. FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS. [Internet] [Doctoral dissertation]. Purdue University; 2015. [cited 2019 Dec 15]. Available from: https://docs.lib.purdue.edu/open_access_dissertations/1448.

Council of Science Editors:

Brust Fernandes T. FUNCTIONAL SELECTIVITY DOWNSTREAM OF Gαi/o-COUPLED RECEPTORS. [Doctoral Dissertation]. Purdue University; 2015. Available from: https://docs.lib.purdue.edu/open_access_dissertations/1448


Purdue University

2. Engle, Staci. Studies of nicotinic acetylcholine receptors containing α4 and α6 subunits in nicotine-induced synaptic plasticity in brain reward areas.

Degree: PhD, Medicinal Chemistry and Molecular Pharmacology, 2016, Purdue University

Tobacco addiction is a serious threat to public health in the United States and abroad, and development of new therapeutic approaches is a major priority. Nicotine, the primary psychoactive compound in tobacco smoke, activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in ventral tegmental area (VTA) dopamine (DA) neurons are crucial for the rewarding and reinforcing properties of nicotine. Nicotine causes cellular changes in VTA DA neurons, including the enhancement of AMPA receptor (AMPAR) function. This enhancement sensitizes the VTA to excitatory input and promotes drug seeking in animal models. However, which nAChR subtype(s) are responsible for initiating these cellular changes is poorly understood. nAChRs containing the α6 subunit (α6* nAChRs) are highly and selectively expressed in DA neurons in the VTA. Therefore, we hypothesized that activation of α6* nAChRs is sufficient to enhance AMPAR function on the surface of VTA DA neurons. To test this, we studied mice expressing hypersensitive, gain-of-function α6 nAChRs (α6L9S mice). We found that low concentrations of nicotine could act selectively through α6* nAChRs to enhance the function of AMPARs on the surface of VTA DA neurons. Through pretreatment with pharmacological inhibitors, we found that NMDA receptors, as well as Ca2+/calmodulin dependent protein kinase II, are also required for this effect. We subsequently expanded these studies to include alcohol because of the high rate of tobacco and alcohol co-abuse. Just as with nicotine, we found that low concentrations of ethanol were sufficient to enhance AMPAR function on VTA DA neurons of α6L9S mice. Because ethanol and nicotine both modulate AMPAR function in a manner involving α6* nAChRs, we tested the hypothesis that low concentrations of ethanol and nicotine combine to modulate AMPAR function. Remarkably, co-incubation of α6L9S brain slices in concentrations of ethanol and nicotine that are sub-threshold when incubated alone resulted in robust enhancement of AMPAR function. Within the VTA, α6 nAChR subunits form nAChRs with and without the α4 nAChR subunit. Therefore, we studied the contribution of α4 nAChR subunits to nicotine-elicited changes in VTA synaptic plasticity. To address this, we removed α4 nAChR subunits from the VTA of adult mice by injecting viral vectors directing expression of Cre recombinase into the VTA of mice with loxP sites flanking the α4 subunit gene. We found that nicotine no longer increases AMPAR function when α4 nAChR subunits are removed from the VTA, indicating a role of nAChRs that contain both α4 and α6 nAChR subunits in VTA synaptic plasticity. Interestingly, we also saw that removing α4 subunits from the VTA of adult mice increases the excitability of VTA DA neurons. We hypothesized that removal of α4* nAChRs from GABAergic neurons in the VTA results in less tonic inhibition of VTA DA neurons. To test this we measured spontaneous inhibitory postsynaptic currents (IPSCs) on VTA DA neurons. Indeed, we saw that the… Advisors/Committee Members: Ryan M Drenan, Val J Watts, Gregory H Hockerman, Edward L Bartlett.

Subjects/Keywords: addiction; alcohol; AMPA; dopamine; nicotine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Engle, S. (2016). Studies of nicotinic acetylcholine receptors containing α4 and α6 subunits in nicotine-induced synaptic plasticity in brain reward areas. (Doctoral Dissertation). Purdue University. Retrieved from https://docs.lib.purdue.edu/open_access_dissertations/1481

Chicago Manual of Style (16th Edition):

Engle, Staci. “Studies of nicotinic acetylcholine receptors containing α4 and α6 subunits in nicotine-induced synaptic plasticity in brain reward areas.” 2016. Doctoral Dissertation, Purdue University. Accessed December 15, 2019. https://docs.lib.purdue.edu/open_access_dissertations/1481.

MLA Handbook (7th Edition):

Engle, Staci. “Studies of nicotinic acetylcholine receptors containing α4 and α6 subunits in nicotine-induced synaptic plasticity in brain reward areas.” 2016. Web. 15 Dec 2019.

Vancouver:

Engle S. Studies of nicotinic acetylcholine receptors containing α4 and α6 subunits in nicotine-induced synaptic plasticity in brain reward areas. [Internet] [Doctoral dissertation]. Purdue University; 2016. [cited 2019 Dec 15]. Available from: https://docs.lib.purdue.edu/open_access_dissertations/1481.

Council of Science Editors:

Engle S. Studies of nicotinic acetylcholine receptors containing α4 and α6 subunits in nicotine-induced synaptic plasticity in brain reward areas. [Doctoral Dissertation]. Purdue University; 2016. Available from: https://docs.lib.purdue.edu/open_access_dissertations/1481

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