Understanding of the details involved in the steps linking activation of receptors on the cell surface with the initiation and control of cell function including growth and differentiation is a fundamental question with implications in a wide variety of improtant processes including clinical situations. A key feature of many of these activation pathways is an elevation of intracellular Ca2+ resulting at least in part from an enhanced entry of Ca2+ from the extracellular medium. The steps responsible for the ectivation of this pathway are presently unknown. To date debate on such mechanisms has focussed on responses under conditions generating a sustained elevation in [Ca2+]. It is now known that under more physiological conditions [Ca2+] responses frequently involve more complex changes including oscillations waves and spatially localized increases in [Ca2+] (so-called 'trigger zones') Ca2+ entry has generally been assumed to play only a minor role in such responses but our recent data suggest this is not so. The evidence further suggests that current models explaining the control of Ca2+ entry during a sustained elevation of [Ca2+] are not adequate to account for the features we have observed for Ca2+ entry during these more complex [Ca2+] responses. Such complex [Ca2+] signals are now believed to be of critical importance in the appropriate activation of mechanisms essential for effective exocrine fluid and protein secretion in acinar cells.
Our aim i s to investigate the role of Ca2+ entry in [Ca2+] oscillations and [Ca2+] trigger zones and the mechanisms controlling it. Digital fluorescence imaging of cells will be employed to obtain spatial information on the relationships between [Ca2+] responses and Ca2+ entry. In addition combined photoncounting microfluorimetry patch-clampong and flash-photolysis will be used for high temporal resolution of {cA2+] responses and their relationships with membrane potential and the activation of membrane currents. Analysis of the nature and roles of Ca2+ entry in such complex responses will significantly further our understanding of signalling pathways in cells. It may also permit the development of pharmacological agents that can be used to manipulate or modify this funddamental and widely distributed process in clinically relevant ways.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM040457-08A3
Application #
2022240
Study Section
Physiology Study Section (PHY)
Project Start
1988-07-01
Project End
2001-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Thompson, Jill L; Zhao, Yue; Stathopulos, Peter B et al. (2018) Phosphorylation-mediated structural changes within the SOAR domain of stromal interaction molecule 1 enable specific activation of distinct Orai channels. J Biol Chem 293:3145-3155
Shuttleworth, Trevor J (2017) Selective activation of distinct Orai channels by STIM1. Cell Calcium 63:40-42
Thompson, Jill L; Shuttleworth, Trevor J (2015) Anchoring protein AKAP79-mediated PKA phosphorylation of STIM1 determines selective activation of the ARC channel, a store-independent Orai channel. J Physiol 593:559-72
Duquette, Mark; Nadler, Monica; Okuhara, Dayne et al. (2014) Members of the thrombospondin gene family bind stromal interaction molecule 1 and regulate calcium channel activity. Matrix Biol 37:15-24
Thompson, Jill L; Shuttleworth, Trevor J (2013) How many Orai's does it take to make a CRAC channel? Sci Rep 3:1961
Thompson, Jill L; Shuttleworth, Trevor J (2013) Molecular basis of activation of the arachidonate-regulated Ca2+ (ARC) channel, a store-independent Orai channel, by plasma membrane STIM1. J Physiol 591:3507-23
Thompson, Jill L; Shuttleworth, Trevor J (2013) Exploring the unique features of the ARC channel, a store-independent Orai channel. Channels (Austin) 7:364-73
Shuttleworth, Trevor J (2012) Orai3--the 'exceptional' Orai? J Physiol 590:241-57
Shuttleworth, Trevor J (2012) Orai channels - new insights, new ideas. J Physiol 590:4155-6
Shuttleworth, Trevor J (2012) STIM and Orai proteins and the non-capacitative ARC channels. Front Biosci (Landmark Ed) 17:847-60

Showing the most recent 10 out of 20 publications