Scheme: University Research Fellowship
Organisation: University of Cambridge
Dates: Oct 2012-Sep 2017
Summary: Every cell, though separated from the outside by a membrane, needs to cope with its ever changing immediate environment marked by continuous arrival and disappearance of numerous stimuli. For this, a very popular way cells use is to vary their internal free calcium concentration ([Ca2+]i). Every heart beat is triggered by a transient increase in Ca2+]i within heart muscle. But calcium also regulates fertilization, growth and death, immune responses, memory formation and much else. What allows Ca2+ to do so many different things simultaneously? The answer is that calcium signals are spatially organised. When the pore of a Ca2+-permeable protein (‘calcium channel’) opens, a tiny cloud of calcium persists around its open mouth so that only proteins that are very nearby experience the signal. Ca2+ can thereby be delivered selectively to specific targets. Many calcium channels, including IP3 receptors (IP3R) are also regulated by Ca2+, and this allows Ca2+ signals to propagate regeneratively as calcium released by one channel ignites the activity of a neighbour. The processes that control the growth of tiny local Ca2+ signals into larger ones that may invade the entire cell are important because they determine what, within the cell, sees the Ca2+ signal.My work is concerned with IP3R. These intracellular Ca2+ channels are expressed in all animal cells and mediate the local and global Ca2+ signals evoked by the many receptors that simulate IP3 formation. I can observe the openings of individual IP3R by measuring the resulting miniscule electrical currents or tiny calcium signals. These methods and molecular manipulation of IP3R will allow me to identify what controls their opening, to examine the mechanisms that allow IP3 to drive IP3R into the small clusters from which regenerative signals arise, and to explore the roles of many additional intracellular signals in regulating lone and clustered IP3R. This will help us understand the basis of versatility of Ca2+ signals.