March 16, 2007 | David F. Coppedge

Cell Calcium Channel: Meet Me at the Gate

All cells use calcium ions for signalling.  The ions flow through specialized gates in the plasma membrane.  Inside the cell, receptors line the endoplasmic reticulum (ER), a kind of subway system where finishing work on proteins is done.  How do the two get together?  They arrange a meeting.
    Richard Lewis, writing in Nature,1 describes how scientists found this out.  It appears that the ER and the calcium channels talk to each other.  When the ER is running low on calcium ions, a messenger molecule goes to the plasma membrane, and starts a process where the channels and a portion of the ER move independently toward a meeting point.  The channels cluster to a spot on the membrane where a fold in the ER joins to meet it, and the calcium ions are delivered right to where they are needed.  In Lewis’s words, “New findings reveal a unique mechanism for channel activation, in which the CRAC channel [calcium release-activated channel2] and its sensor migrate independently to closely apposed sites of interaction in the ER and the plasma membrane.”
    What are these processes good for?  The short list includes: secretion, motility, gene expression, cell growth, and activation of the T cell response to antigens.  This emerging picture comes after “years of frustration” looking for the mechanism by which this interaction worked.  They finally found the secret using forward and reverse gene activation methods.
    In the paper, Lewis included a cartoon diagram of the play-by-play process.  He called it a kind of “molecular choreography” in which the cell performs “assembly on demand”.  Using the word “Remarkably” twice in the paper, he commented on the significance of this apparatus: “This kind of choreographic activation mechanism, in which a channel and its sensor migrate within distinct membranes to reach a common interaction site, is unprecedented.”  But why don’t the receptor and channel just stay put in close proximity?  It’s likely, he explains, that the oscillations in calcium activity introduce delays that create local signaling domains, enhancing the specificity of calcium signaling for particular purposes.
    The picture may be more complex than it looks already.  The signaling proteins he described may be part of multi-protein complexes.  Something, for instance, has to give the open sesame password to the channel.  Other activators may be required to call the components to the rendezvous site.
    Lewis did not mention evolution in this paper, except to note twice that parts of the system are conserved (i.e., unevolved) from Drosophila (fruit flies) to humans.  Since such vastly diverse organisms are composed of cells, and all cells employ calcium signalling, this probably implies the system is conserved throughout the eukaryotic kingdom if not all life.

1Richard S. Lewis, “The molecular choreography of a store-operated calcium channel,” Nature 446, 284-287 (15 March 2007) | doi:10.1038/nature05637.
2CRAC is unusual among the family of calcium channels.  Lewis describes it: “The unusual characteristics of this channel have long intrigued ion-channel biophysicists; it selects for Ca2+ just as well as CaV channels but conducts Ca2+ >100 times more slowly, is inactivated by intracellular Ca2+ on timescales separated by three orders of magnitude, and requires extracellular Ca2+ to be fully active.”  The reasons for these “unique channel properties” are still under investigation.  It will take time to obtain a “global view of the molecular workings of store-operated channels and their physiological roles.”  The overall effectiveness of the system in vital roles suggests there is a reason for its slow activation compared to other calcium channels.

Since Lewis called this remarkable, let’s give it some remarks.  How could such a process evolve?  Multiple protein parts are needed, and they need to not only match one another’s conformation, but migrate to exact points where other proteins (or protein complexes) are independently migrating simultaneously.  He admitted that this process shows no evolutionary modification throughout biology.  How could such a precision ballet arise by chance?  Ballet needs a choreographer.  Lewis did not need evolutionary theory for this paper.  If evolutionists had a ready answer to how this evolved, they surely would not keep silent about it as they always do when investigating the details of biology (e.g., 08/28/2006, 04/05/2006, 03/12/2006).

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