Researchers Open the Gates

January 5, 2009

If you were among the millions of Americans this weekend that went to the movies, chances are you spent a few minutes in line waiting for patrons from the earlier show to exit the theater.  For most, the wait in front of the gated door wasn’t such a big deal.  Theaters must move ‘em out before they can pack ‘em back in.   This same concept of efflux and influx holds true for calcium-signaling cells in the body.  They must first expel their internal stores of calcium before allowing an influx of new calcium ions.  This biochemical process, common in myriad physiological processes from muscle contraction to saliva secretion, is initiated through a protein receptor that activates the opening and/or closing of a gated pore in the cell outer membrane.  This type of pore is called a store-operated calcium channel, or SOC.  In recent years, scientists have identified two major varieties of SOCs on the plasma membrane, the cell’s envelope.  One is called the TRPC channel, while the other is known as the Orai channel.  Interestingly, both are gated by the same calcium sensor called STIM1 that reside in the endoplasmic reticulum.

That’s where the molecular information grows thin.  Researchers would like to know exactly how STIM1 gates the two channels and whether the protein does so in exactly the same way.  In the November 7 issue of the journal Molecular Cell, NIDCR grantees and colleagues begin to answer both questions.  They found that STIM1 gates TRPC channels through an electrostatic interaction.  In this case, a positively charged region of STIM1 specifically interacts in a lock-and-key manner with two negatively charged and highly conserved aspartate residues of the TRPC channel.  However, the scientists found that’s not the case in the Orai channels.  STIM1 relies on a different and still undetermined mechanism.  The discovery of the electrostatic gating mechanism provides a novel and invaluable lead to understand the operation of the TRPC channel.  It also clears the way for additional research to fine tune calcium signaling at the cellular level, work that can be exploited in oral health possibly to improve salivary flow.