Counting functional IP3 receptors into the plasma membrane

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The protective membrane that surrounds every cell provides the barrier needed to allow each cell to maintain a composition different from that of its environment, but it also isolates the cell interior from important extracellular signals. The latter problem is resolved by inserting proteins into the membrane that specifically recognise extracellular signals and then transduce them into intracellular signals capable of controlling cellular activity. Ca is the most important of these intracellular signals, not least because it is present at much lower concentration within the cell than on the opposite side of the membranes that either surround the cell or the organelles within it. The opening of Ca channels within these membranes is the most common means whereby extracellular stimuli evoke an increase in intracellular Ca concentration. For many years we have known that IP3 receptors are the most important and widely expressed Ca channels within the membranes of intracellular stores, but our recent work suggests that they are also functionally expressed in the membrane (PM) that surrounds the cell, where they provide the route for much of the Ca that flows into the cell from outside. To our great surprise, each cell absolutely reliably counts 1-3 IP3R into the PM from the many 1000s expressed within the cell. Such counting is important because otherwise IP3R in the PM might cause the cell to be overwhelmed with Ca and that would be toxic. But how can a cell so reliably count so few proteins into the membrane surrounding each cell? This project aims to answer that question.