E-Conference: Defining Calcium Entry Signals
How many stores are there?
11 June 2004
Reinholt, there is no doubt that the system is complex but one has to start with a "simplistic interpretation" to create a robust working hypothesis that attempts to bring together most of the salient observations. The main object of my working hypothesis was to describe a mechanism of Ca2+ entry and then to explain how it might function in the development of a typical Ca2+ transient. Many of the points that you made seemed to me to be exactly in line with this hypothesis except for two points. Firstly, you propose the existence of two stores, the CRAC store and the much larger release store and I shall discuss this later. Secondly, you do not mention the role for lumenal Ca2+, which I consider as an important component of the hypothesis in that it sets the sensitivity of IP3Rs. With these two points in mind, let me comment on your three points:
You seem to be concerned about why there is no plateau phase during this threshold condition. As I argued before, the reason why there is no plateau phase is because the SERCA pumps are very efficient at taking up the Ca2+ and it this uptake that sensitizes the IP3Rs.
Perhaps the main difference in our interpretation is whether there is a single or two separate stores (a CRAC store and a larger release store). I dealt with this question in my comments. It seems that we both agree that there has to be two functional stores and the question therefore is whether or not they are physically separate. I argue that the ER is continuous but that it can be separated physiologically into two regions. The junctional zone that responds to the high dose of IP3 near the membrane and the remainder of the store where the uncoupled IP3Rs are located. At physiological agonist concentrations, these uncoupled receptors do not respond directly to IP3 because the concentration is too low. Therefore, before they can respond to the low ambient IP3 level they have to be sensitized by the Ca2+ coming in from the outside through the entry pathway.
As I mentioned in my comments, the problem with having two separate stores is what happens when the small CRAC store fills up and the main release pool is still empty?
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882