Abstract
The versatility and universality of Ca(2+) signals stem from the breadth of their spatial and temporal dynamics. Spatially, Ca(2+) signalling is well studied in the microdomain scale, close to a Ca(2+) channel, and at the whole-cell level. However, little is known about how local Ca(2+) signals are regulated to specifically activate spatially distant effectors without a global Ca(2+) rise. Here we show that an intricate coupling between the inositol 1,4,5 trisphosphate (IP3) receptor, SERCA pump and store-operated Ca(2+) entry (SOCE) allows for efficient mid-range Ca(2+) signalling. Ca(2+) flowing through SOCE is taken up into the ER lumen by the SERCA pump, only to be re-released by IP3Rs to activate distal Ca(2+)-activated Cl(-) channels (CaCCs). This CaCC regulation contributes to setting the membrane potential of the cell. Hence functional coupling between SOCE, SERCA and IP3R limits local Ca(2+) diffusion and funnels Ca(2+) through the ER lumen to activate a spatially separate Ca(2+) effector.
Highlights
The versatility and universality of Ca2 þ signals stem from the breadth of their spatial and temporal dynamics
Localized Ca2 þ signals are due to Ca2 þ flowing through Ca2 þ channels that creates a Ca2 þ microdomain with high Ca2 þ concentrations at the mouth of the channel, which gradually dissipates as Ca2 þ is buffered and is diluted as it diffuses into a larger volume[5,6]
Using a simple three-step voltage protocol Ca2 þ -activated Cl À channels (CaCCs) allow for the simultaneous monitoring of Ca2 þ release from stores through IP3Rs and Ca2 þ influx through store-operated Ca2 þ entry (SOCE) (Fig. 1a)[25,40]
Summary
The versatility and universality of Ca2 þ signals stem from the breadth of their spatial and temporal dynamics. It is possible that mid-range Ca2 þ signalling can be achieved by modulating the flux through a channel (or channel cluster) to saturate local Ca2 þ buffers, and allow limited spread of the Ca2 þ signal It is unclear how cells would be able to tightly control the Ca2 þ spatial spread, especially with the potential of Ca2 þ -induced Ca2 þ release through ryanodine and IP3 polarized rpeacnecprteoartsic(aIPci3nRasr)1c7e.llsOins ethewseoll--cdaelfilendedCam[2] þechtuannnisemllinign, where Ca2 þ entering through basolateral Ca2 þ channels flows through endoplasmic reticulum (ER) tunnels across the entire acinar cell to refill apical Ca2 þ stores[18,19,20]. It is clear that mid-range Ca2 þ signalling is functional in cells, the mechanisms underlying it remain obscure
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