E-Conference: Defining Calcium Entry Signals
Comments on cellular domains that contribute to calcium entry events
8 June 2004
Kenneth L. Byron
Let me first endorse Mike's arguments that we must consider physiological concentrations of agonists to understand the mechanisms governing Ca2+ entry. Despite the practical difficulties that are involved in resolving submaximal signaling events in the laboratory, work from a number of labs, including my own, have revealed some remarkable differences in Ca2+ signaling patterns comparing low and high agonist concentrations.
I really wanted to ask Mike a couple of questions about the conformational coupling model, which I have always found appealing. I have two questions related to your vision of the cellular architecture. First, there is more and more experimental evidence supporting mechanisms for activation of Ca2+ entry via signaling pathways (e.g. CIF, iPLA2) that can apparently operate independently of PLC, IP3 receptors, or Ca2+ release. Do you think these mechanisms converge on the same cellular structures that are involved in conformational coupling?
Second, the arrangement of Ca2+ transporters (Ca2+-ATPases, Na+/Ca2+ exchangers) and Ca2+ release sites is not clearly described, so I wonder if you would expand on your ideas about which subsets of IP3 receptors are functioning as release channels at different agonist concentrations and the question of whether there is a particular orientation that would direct the released Ca2+ toward its presumed effector targets, which may be away from the plasma membrane. Are SERCA pumps arranged to buffer Ca2+ that diffuses toward the membrane? It seems as though your model would necessarily have the Ca2+ entry directed toward the IP3 receptors of the junctional ER and also perhaps toward a concentration of SERCA pumps that would act to refill the stores.
If Ca2+ entry precedes Ca2+ release, does the local elevation of [Ca2+]i sensitize the junctional IP3 receptors or act as a co-agonist to activate the release channels? Or is there a different subset of release channels away from the junction that allow the bulk of released Ca2+ to more effectively reach its targets?
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