Indu Ambudkar, Ph.D.
Molecular Physiology and Therapeutics Branch
Building 10, Room 1N113
10 Center Drive
Bethesda, MD 20892
Neurotransmitter regulation of salivary secretion is mediated by a sustained increase in intracellular [Ca2+] ([Ca2+]i) which is due to store-operated Ca2+ entry (SOCE), activated in response to IP3-depletion of ER calcium stores. This sustained elevation in [Ca2+]i regulates a number of key ion flux systems which concertedly drive salivary gland (SG) fluid secretion. Emerging studies reveal that cellular Ca2+, and more specifically Ca2+ entry, also regulates key mechanisms associated with gene expression, cell growth, differentiation, inflammation, and cell death. Our long term goal is to define the components that mediate and regulate Ca2+ entry into salivary gland cells and characterize the role of these in normal physiology as well as dysfunction/disease of salivary glands.
Our studies utilize a variety of approaches, including electrophysiology, cellular imaging, molecular biology, as well as biochemistry to determine the molecular basis of Ca2+ entry in salivary gland acini and the role of Ca2+ entry in fluid secretion. Our recent and ongoing studies are directed towards identifying the function, regulation, trafficking and assembly of the transient receptor potential channel, TRPC1. We have provided evidence that TRPC1 is an essential component of the agonist-stimulated Ca2+ influx mechanism that is required for sustained saliva secretion. We have identified two other important components of this mechanism, the calcium channel, Orai1, and the ER regulator of calcium channels, STIM1. Current studies are directed to understand and define the individual contributions of TRPC1 and Orai1 to salivary fluid secretion. We are also interested in identifying the regulation of the water channel, AQP5, during stimulation of the gland and secretion. Our work has led to the identification of TRPV4 as an essential TRP channel that is involved in cellular volume regulation. In addition other TRPC channels, TRPC3 and TRPC6, could also have important role in regulating other aspects of salivary gland function. These studies are ongoing.
We are also utilizing proteomic techniques to elucidate possible protein-protein interactions involving TRPC1, Orai1, and STIM1. By using the SILAC method and a shot-gun approach, we get a global read-out of the proteome associated with the channels in resting and stimulated conditions. Several interesting candidates have been identified and are currently being validated. Another approach to examine downstream effectors of Ca2+ signaling is by cDNA array analysis. We aim to identify key cell signaling networks that are regulated by Ca2+ that participate in salivary gland physiology or pathophysiology.
Another major area of focus is salivary gland damage associated with radiation treatment as well as Sjögren's syndrome. Major efforts are directed to understanding the role of the ROS-sensitive cation channel TRPM2 in salivary gland damage induced by irradiation and inflammation. Functional studies are being carried out to demonstrate the role of this channel in these processes. We propose that TRPM2 is a potentially useful target in strategies of protection of salivary gland function. Studies are also ongoing to look at the status of STIM1, Orai1, and TRPC channel proteins in pSS salivary glands and lymphocytes. The strategy is to modify locally within the salivary gland, by delivery of viral vectors, the expression of specific proteins (knock down or overexpression) and then assess the effects in normal secretion and in salivary dysfunction.
- 1973 - B.Sc. (Biology), Isabella Thoburn College, Lucknow, India
- 1975 - M.Sc. (Biochemistry), Lucknow University, Lucknow, India
- 1980 - Ph.D. (Biochemistry), Madurai Kamaraj University, Madurai, India
- 2007 - Chief, GTTB, NIDCR, NIH
- 2006–2007 - Acting Chief, MPTB, NIDCR, NIH
- 1993–present - Chief, Secretory Physiology Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH
- 1988–1993 - Senior Staff Fellow (Tenure-track), Clinical Investigations and Patient Care Branch, NIDR, NIH
- 1991–1996 - Adjunct Assistant Professor, Department of Pathology, University of Maryland, School of Medicine, Baltimore, MD
- 1985–1988 - Visiting Associate, Clinical Investigations and Patient Care Branch, NIDR, NIH, Bethesda, MD
- 1984–1985 - Research Assistant Professor, Department of Pathology, School of Medicine, Baltimore, MD
- 1980–1983 - Research Associate, Department of Biological Chemistry, University of Maryland, School of Medicine, Baltimore, MD
- NIH Merit Award, 2000
- Member, Oral Biology and Medicine, Study Section, 1997-2000
- Administrative Chair WSA Committee, NIH (2005-2008)
- Woman Scientists' Advisor to the Scientific Director, NIDR, 1993-1998, 2002-present
- Member of the NIH Women's Advisory group
- Co-Chair, NIH-Calcium Interest Group, 1997-present
- Chair, Gordon Conference on Calcium Signaling, 2007
- Co-Chair; Gordon Conference on Calcium Signaling, 2005
- Vice-Chair Elect; Salivary gland and excocrine secretion GRC, 2011
- Chair Elect; Salivary gland and excocrine secretion GRC, 2013
- Faculty Member, Faculty of 1000 Biology
- Review Editorial Board of Frontiers in Pharmacology of Ion Channel and Channelopathies
- Editorial Board Member: Cell Calcium
- Editorial Board member: Journal of Biological Chemistry
- Member Editorial Board, Journal of Dental Research. 1996-1999
- Member Editorial Board, Membrane Biochemistry. 1991-1996
Cheng KT, Liu X, Ong HL, Swaim W, Ambudkar IS. Local Ca²+ entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca²+ signals required for specific cell functions. PLoS Biol. 2011;9(3):e1001025.
Liu X, Cheng KT, Bandyopadhyay BC, Pani B, Dietrich A, Paria BC, Swaim WD, Beech D, Yildrim E, Singh BB, Birnbaumer L, Ambudkar IS. Attenuation of store-operated Ca2+ current impairs salivary gland fluid secretion in TRPC1(-/-) mice. Proc Natl Acad Sci U S A. 2007;104(44):17542-7.
Liu X, Gong B, de Souza LB, Ong HL, Subedi KP, Cheng KT, Swaim W, Zheng C, Mori Y, Ambudkar IS. Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase-3 and loss of SOCE through a TRPM2-dependent pathway. Sci Signal. 2017;10(482).
Liu X, Cotrim A, Teos L, Zheng C, Swaim W, Mitchell J, Mori Y, Ambudkar I. Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction. Nat Commun. 2013;4:1515.
Ong HL, de Souza LB, Zheng C, Cheng KT, Liu X, Goldsmith CM, Feske S, Ambudkar IS. STIM2 enhances receptor-stimulated Ca²⁺ signaling by promoting recruitment of STIM1 to the endoplasmic reticulum-plasma membrane junctions. Sci Signal. 2015;8(359):ra3.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on August 8th, 2017