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Molecular and cellular mechanisms of store-operated calcium channels

Award Number: R35GM149305
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 03/29/2026
AWARD TERMINATION DATE: 03/20/2026

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Molecular and cellular mechanisms of store-operated calcium channels - Store-operated Ca2+ entry (SOCE) generates Ca2+ signals that are critical for many physiological processes, from immune cell activation and differentiation to muscle activity, secretion, and motility. Store-operated Ca2+ channels (SOCs) are activated by receptors that deplete Ca2+ from the ER; the loss of Ca2+ is sensed by STIM1, which then accumulates at ER-plasma membrane (ER-PM) junctions where it binds, traps, and activates calcium-selective Orai channels diffusing in the PM. Gain-of-function and loss-of-function mutations in this pathway have both been connected to serious human diseases, underscoring the critical importance of precise regulation. The long-term goal of our laboratory is to understand the molecular basis of SOC properties and regulation as well as their cellular roles. While the overall organization of the SOCE pathway is now known and many of the underlying proteins have been identified, major gaps still exist in our understanding of how they act to regulate SOCE location and amplitude. Over the next five years we aim to investigate three fundamental processes that regulate calcium influx through SOCs. (1) The dynamics of ER-PM junctions. These junctions where the ER closely approaches the PM are the only sites in the cell where STIM can bind and activate Orai, such that their size, abundance and location determine both the amplitude and location of Ca2+ entry. While a host of tethering proteins at junctional sites is known, their specific roles in junction initiation vs. turnover is unclear. By monitoring the appearance and removal of ER-PM junctions in living cells with fluorescent markers we will distinguish the different contributions of known tethering proteins to the initiation, lifetime and turnover rate of new junctions, as well as their ability to conduct SOCE. (2) The mechanism of STIM1 activation and its interaction with Orai1. The cytosolic domain of STIM1 undergoes a massive conformational change after ER Ca2+ depletion in order to unmask and extend the CRAC activation domain (CAD) to activate Orai in the plasma membrane. By studying STIM1 with single-molecule fluorescence and crosslinking techniques we aim to identify steps in the activation process and intermediate states that may help mitigate the energetic cost of unfolding and refolding STIM1. Similar approaches will be applied to determine basic features of the STIM-Orai interaction - the stoichiometry of the STIM-Orai complex, the conformation of CAD in the bound state, and the binding interface itself – which are currently not understood. (3) A molecular mechanism for Ca2+-dependent inactivation (CDI). Despite progress in identifying multiple residues and domains in STIM and Orai that are critical for CDI, an integrated mechanism is still lacking. We will use a pore accessibility assay to localize the position of the inactivation gate, and explore functional and physical interactions of CDI domains to understand how they cooperate to bring about CDI. Overall, the results of our studies will reveal fundamental cellular and molecular mechanisms that control the strength of store-operated calcium signals in diverse cells, and may suggest new strategies for regulating them to explore cellular functions and develop new treatments for human disease.


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: 2026 ( Subtotal = $0 )
2026	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	3/20/2026	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $554,867 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	3	3/28/2025	NON-COMPETING CONTINUATION	$554,867
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $554,867

Issue Date FY: 2024 ( Subtotal = $554,867 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	2	5/21/2024	NON-COMPETING CONTINUATION	$55,486
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	4/4/2024	NON-COMPETING CONTINUATION	$499,381
														Subtotal = $554,867

Issue Date FY: 2023 ( Subtotal = $555,470 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	4/17/2023	NEW	$555,470
														Subtotal = $555,470

Grand Total All Awards = $1,665,204

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Molecular and cellular mechanisms of store-operated calcium channels

Award Number: R35GM149305

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 03/29/2026

AWARD TERMINATION DATE: 03/20/2026

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