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Reciprocal mGluR5-CaMKII regulation

Award Number: F31MH109196
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2018

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Reciprocal mGluR5-CaMKII regulation - ¿ DESCRIPTION (provided by applicant): Calcium/calmodulin-dependent kinase II (CaMKII) is a highly abundant serine/threonine kinase in the brain. Calcium signals, caused by influx via various plasma membrane ion channels/receptors or release from intracellular stores, activates distinct sub-populations of CaMKII that are coupled to specific downstream targets. There is a growing appreciation for the importance of direct interactions of activated CaMKII with other proteins in multiple CaMKII functions, such as feedback regulation of plasma membrane channels/receptors, and for normal synaptic plasticity. Relatively few CaMKII-associated proteins are known to preferentially interact with inactive CaMKII, and their functional roles are poorly understood. Moreover, molecular mechanisms underlying the coupling of CaMKII to the G-protein coupled receptors (GPCRs) that stimulate the release of intracellular calcium are poorly characterized. This project characterizes a novel interaction of inactive CaMKII with the C-terminal domain (CTD) of metabotropic glutamate receptor 5 (mGlu5), and its role in reciprocal regulation between CaMKII and mGlu5. Preliminary data show that CaMKII associates with mGlu5 in brain extracts, consistent with a prior report. I confirmed this interaction of full-length proteins in co-transfected HEK293 cells. I have shown that inactive CaMKII directly interacts with the CTD of mGlu5, and that this interaction is disrupted by calcium/calmodulin. Furthermore, binding to the mGluR5 CTD enhances the apparent cooperativity for CaMKII activation by calcium/calmodulin in vitro, causing it to be activated in a more switch-like manner. The activated CaMKII can phosphorylate the CTD. The following aims will test my overarching hypothesis that CaMKII-mGluR5 interaction is important for a reciprocal regulatory mechanism in which CaMKII modulates downstream mGluR5 signaling and mGluR5 modulates CaMKII activation. Aim 1 will identify molecular determinants for inactive CaMKII binding to the CTD of mGlu5, identify CaMKII phosphorylation sites in the CTD, and determine the effects of CaMKII on downstream mGlu5 signaling to calcium release from intracellular stores, MAP kinase activation, and initiation of protein translation using specific CaMKII inhibitors and mice with a genetic mutation that inhibits autonomous CaMKII activity. Aim 2 will define the coupling of mGluR5 to activate CaMKII in vitro, and in transfected HEK293 cells. These studies will also CaMKII regulation in brain slices from WT and mGluR5 knockout mice. This proposal also outlines plans for professional training through technical skill development, presentation of my work to diverse audiences, and writing and editing of manuscripts and grants. Progress toward these goals will be documented through regular meetings with a Ph.D. Dissertation committee, as well as by yearly completion of an individual development plan. Thus, the training plan will foster my development as a desirable candidate for top-flight postdoctoral positions and an independent research career.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = -$2,420 )
2021	2017	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Mental Health Research Grants	000	2	12/28/2020	NON-COMPETING CONTINUATION	-$2,420
														Subtotal = -$2,420

Issue Date FY: 2017 ( Subtotal = $28,702 )
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Mental Health Research Grants	001	2	7/26/2017	NON-COMPETING CONTINUATION	$924
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Mental Health Research Grants	000	2	2/24/2017	NON-COMPETING CONTINUATION	$27,778
														Subtotal = $28,702

Issue Date FY: 2015 ( Subtotal = $27,778 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	1	9/7/2015	NEW	$27,778
														Subtotal = $27,778

Grand Total All Awards = $54,060

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Reciprocal mGluR5-CaMKII regulation

Award Number: F31MH109196

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2018

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