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Regulation of sensory TRP channels by phospholipids and G-proteins

Award Number: R01NS055159
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Regulation of sensory TRP channels by phospholipids and G-proteins - The topic of the original funded grant proposal was phosphoinositide regulation of the heat- and capsaicin sensitive TRPV1, and the cold- and menthol-sensitive TRPM8 channels. The current renewal proposal continues to study phosphoinositide regulation of TRPV1, and addresses an important unsolved problem, brought to light by a recent higher resolution structure in lipid nanodiscs, which found that the capsaicin/vanilloid binding site is occupied by a phosphoinositide, and proposed that it stabilizes the channel in the resting state, and vanilloids activate TRPV1 by replacing the lipid. PI(4,5)P2 and PI(4)P however are well established positive cofactors/regulators of TRPV1, which is difficult to reconcile with this model. The exact nature of the phosphoinositide lipid, however, is not well resolved in the structure. In Aim1 we will elucidate the nature of the phosphoinositide in the vanilloid binding site, using the combination of computational modeling, site directed mutagenesis, whole cell and excised patch electrophysiology and planar lipid bilayers. The TRPM3 ion channel is expressed in Dorsal Root Ganglion (DRG) neurons; its genetic deletion in mice results in altered sensitivity to noxious heat. TRPM3 is activated by heat, and chemical agonists, such as Pregnenolone Sulphate (PregS) and CIM0216. We found that this channel requires phosphoinositides for activity, and we also found that agonists of phospholipase C (PLC)-coupled receptors inhibit TRPM3. This inhibition, however, was not alleviated by intracellular delivery of excess PI(4,5)P2, and was reduced by a protein that binds the βγ subunits of heterotrimeric G-proteins (Gβγ sink). This finding points to the dominance of Gβγ signaling over PLC activation in regulating TRPM3. Activation of Gi-coupled receptors that do not activate PLC also robustly inhibited TRPM3 activity, and the effect was reduced by Gβγ sinks. Co-expression of Gβγ in intact cells, and application of purified Gβγ to excised inside-out patches also inhibited TRPM3, and we detected biochemical interaction between TRPM3 and Gβ by co-immunoprecipitation. These data suggest that Gβγ subunits are direct negative regulators of TRPM3. We also found that activation of endogenous Gi- coupled GABAB and opioid receptors inhibited PregS-induced Ca2+ signals in DRG neurons. In Aims 2 and 3, we will test predictions of our model of TRPM3 regulation, and elucidate the molecular determinants of this effect using a combination of molecular biology, patch clamp, planar lipid bilayer, skin-nerve electrophysiology, fluorescence-based cellular imaging techniques, and animal behavior.


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: 2024 ( Subtotal = $0 )
2024	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	5/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $472,585 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	5/18/2022	NON-COMPETING CONTINUATION	$472,585
														Subtotal = $472,585

Issue Date FY: 2021 ( Subtotal = $472,585 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	5/14/2021	NON-COMPETING CONTINUATION	$472,585
														Subtotal = $472,585

Issue Date FY: 2020 ( Subtotal = $472,585 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	5/18/2020	NON-COMPETING CONTINUATION	$472,585
														Subtotal = $472,585

Issue Date FY: 2019 ( Subtotal = $592,376 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	5/8/2019	NON-COMPETING CONTINUATION	$592,376
2019	2016	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/15/2019	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $592,376

Issue Date FY: 2018 ( Subtotal = $636,626 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	8/2/2018	COMPETING CONTINUATION	$636,626
														Subtotal = $636,626

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	9/18/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $412,901 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/7/2016	EXTENSION WITH OR WITHOUT FUNDS	$412,901
														Subtotal = $412,901

Issue Date FY: 2015 ( Subtotal = $412,901 )
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	8/7/2015	SUPPLEMENT FOR EXPANSION	$65,088
2015	2015	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	6/26/2015	NON-COMPETING CONTINUATION	$347,813
														Subtotal = $412,901

Issue Date FY: 2014 ( Subtotal = $344,334 )
2014	2014	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	6/17/2014	NON-COMPETING CONTINUATION	$344,334
														Subtotal = $344,334

Issue Date FY: 2013 ( Subtotal = $347,813 )
2013	2013	Rutgers, The State Univ Biomedical & HEALTH Sciences	65 Davidson Road	Piscataway	NJ	08554		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/16/2013	COMPETING CONTINUATION	$347,813
														Subtotal = $347,813

Issue Date FY: 2011 ( Subtotal = $334,425 )
2011	2011	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/31/2011	NON-COMPETING CONTINUATION	$334,425
														Subtotal = $334,425

Issue Date FY: 2010 ( Subtotal = $337,838 )
2010	2010	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/17/2010	NON-COMPETING CONTINUATION	$337,838
														Subtotal = $337,838

Issue Date FY: 2009 ( Subtotal = $341,250 )
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/6/2009	NON-COMPETING CONTINUATION	$341,250
														Subtotal = $341,250

Issue Date FY: 2008 ( Subtotal = $341,250 )
2008	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/13/2008	NON-COMPETING CONTINUATION	$341,250
														Subtotal = $341,250

Issue Date FY: 2007 ( Subtotal = $341,250 )
2007	2007	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/6/2007	NEW	$341,250
														Subtotal = $341,250

Grand Total All Awards = $5,860,719

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Regulation of sensory TRP channels by phospholipids and G-proteins

Award Number: R01NS055159

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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