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Molecular Regulation of Metabotropic Glutamate Receptors in Striatal Neurons

Award Number: R01MH061469
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Project Summary Metabotropic glutamate (mGlu) receptor 2 is a presynaptic receptor enriched in active zones of glutamatergic nerve terminals within the striatum and is pivotal for brain functions and some mental illnesses. Recently, we found that Ca2+/calmodulin-dependent protein kinase II (CaMKII) directly binds to mGlu2 receptors and phosphorylates mGlu2 receptors at a threonine residue in the intracellular C-terminal tail. These findings for the first time reveal the mGlu2 receptor as a direct substrate of CaMKII. Encouraged by this novel discovery, we propose this renewal application to systematically study this previously unrecognized CaMKII-mGlu2 coupling and to explore roles of CaMKII and mGlu2 receptors in the pathogenesis and symptomatology of a common mental illness. Our hypothesis is that CaMKII regulates mGlu2 receptors and links mGlu2 plasticity to depression-like behavior. Using multidisciplinary approaches, this hypothesis will be tested both in vitro and in vivo in the following four inter-supportive Aims. Aim I will characterize fundamental protein biochemistry of the CaMKII-mGlu2 interplay in vitro. Aim II will define the regulation of CaMKII-mGlu2 interactions and mGlu2 receptor phosphorylation by changing Ca2+ signals in striatal glutamatergic nerve terminals in vivo. Aim III will explore functional roles of CaMKII in modulating trafficking and subcellular expression of mGlu2 receptors and in controlling the efficacy of various mGlu2 signaling events. Aim IV will first monitor long- lasting neuroadaptations of the striatal CaMKII-mGlu2 system in response to prolonged social isolation in adult rats, a chronic stress paradigm modeling anhedonic depression in adulthood animals. Aim IV will then clarify functional roles of CaMKII-mGlu2 interactions in the isolation- induced depression-like behavior. Results achieved here will conceptually advance our current understanding of a phosphorylation-dependent mechanism in regulating glutamate receptor signaling at presynaptic sites. They will also ultimately contribute to the development of novel pharmacotherapies, by targeting CaMKII and mGlu2 receptors, for the treatment of core symptoms of depression.


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: 2023 ( Subtotal = $387,500 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	1011 E 51ST ST	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	23	4/25/2023	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2022 ( Subtotal = $387,500 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	22	4/29/2022	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2021 ( Subtotal = $387,500 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	21	4/6/2021	NON-COMPETING CONTINUATION	$387,500
2021	2019	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	19	7/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,500

Issue Date FY: 2020 ( Subtotal = $387,500 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	20	6/26/2020	COMPETING CONTINUATION	$387,500
2020	2019	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	19	6/26/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,500

Issue Date FY: 2019 ( Subtotal = $377,500 )
2019	2019	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	19	1/25/2019	NON-COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2018 ( Subtotal = $377,500 )
2018	2018	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	18	6/4/2018	NON-COMPETING CONTINUATION	$37,750
2018	2018	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	18	2/24/2018	NON-COMPETING CONTINUATION	$339,750
														Subtotal = $377,500

Issue Date FY: 2017 ( Subtotal = $377,500 )
2017	2017	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	000	17	3/1/2017	NON-COMPETING CONTINUATION	$339,750
2017	2017	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Mental Health Research Grants	001	17	7/17/2017	NON-COMPETING CONTINUATION	$37,750
														Subtotal = $377,500

Issue Date FY: 2016 ( Subtotal = $377,500 )
2016	2016	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	16	2/27/2016	NON-COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2015 ( Subtotal = $377,500 )
2015	2015	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	15	3/4/2015	COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2014 ( Subtotal = $371,250 )
2014	2014	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	14	2/18/2014	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2013 ( Subtotal = $356,400 )
2013	2013	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	001	13	6/10/2013	NON-COMPETING CONTINUATION	$22,275
2013	2013	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	13	2/13/2013	NON-COMPETING CONTINUATION	$334,125
														Subtotal = $356,400

Issue Date FY: 2012 ( Subtotal = $371,250 )
2012	2012	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	12	2/2/2012	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2011 ( Subtotal = $371,250 )
2011	2011	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	001	11	7/20/2011	NON-COMPETING CONTINUATION	$33,750
2011	2011	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	11	3/24/2011	NON-COMPETING CONTINUATION	$337,500
														Subtotal = $371,250

Issue Date FY: 2010 ( Subtotal = $375,000 )
2010	2010	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	10	5/14/2010	COMPETING CONTINUATION	$375,000
2010	2009	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	001	9	5/14/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $375,000

Issue Date FY: 2009 ( Subtotal = $282,250 )
2009	2009	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	001	9	7/13/2009	NON-COMPETING CONTINUATION	$28,225
2009	2009	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	9	11/10/2008	NON-COMPETING CONTINUATION	$254,025
														Subtotal = $282,250

Issue Date FY: 2008 ( Subtotal = $282,250 )
2008	2008	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	8	11/5/2007	NON-COMPETING CONTINUATION	$282,250
														Subtotal = $282,250

Issue Date FY: 2007 ( Subtotal = $282,250 )
2007	2007	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	7	11/30/2006	NON-COMPETING CONTINUATION	$282,250
														Subtotal = $282,250

Issue Date FY: 2006 ( Subtotal = $290,679 )
2006	2006	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	6	11/30/2005	NON-COMPETING CONTINUATION	$290,679
														Subtotal = $290,679

Issue Date FY: 2005 ( Subtotal = $297,675 )
2005	2005	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	5	1/24/2005	COMPETING CONTINUATION	$297,675
														Subtotal = $297,675

Issue Date FY: 2004 ( Subtotal = $181,250 )
2004	2004	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	4	12/5/2003	NON-COMPETING CONTINUATION	$181,250
														Subtotal = $181,250

Issue Date FY: 2003 ( Subtotal = $179,919 )
2003	2003	UNIVERSITY OF MISSOURI, SCHOOL OF MEDICINE	222 HOLMES STREET	KANSAS CITY	MO	64108	JACKSON	USA	Mental Health Research Grants	000	3		NON-COMPETING CONTINUATION	$179,919
														Subtotal = $179,919

Grand Total All Awards = $7,502,282

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Molecular Regulation of Metabotropic Glutamate Receptors in Striatal Neurons

Award Number: R01MH061469

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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