Cellular cartography.

The electronic chips that have revolutionized our world are architectural marvels. Transistors, ~50 nm long, are etched in siliconwith remarkable precision. We who work with floppy biological cells in a watery world might be forgiven for thinking that such precision and order are not achievable and may not be necessary for the proper functioning of living cells. Immunofluorescence images of cells often give one the impression that proteins are cast about willy-nilly. A precision of a few thousand nanometers seems to be good enough. Call this biological sloppiness or robustness. But nanometers matter. The recent history of cardiac muscle tells us why. The ryanodine receptor (RyR, the intracellular Ca2þ release channel of the sarcoplasmic reticulum, SR) has been known since 1970 to possess the property of Ca2þ-induced Ca2þ release: Ca2þ entering the cell through the L-type Ca2þ channel (CaV1.2) increases the open probability of the nearby RyRs causing Ca2þ release from SR, further increasing the Ca2þ concentration at the mouth of RyR. One would immediately predict that a wave of propagating Ca2þ release would occur and that Ca2þ release would be all-or-none. Paradoxically, the strength of contraction (largely a function of the amount of Ca2þ released from the SR) is smoothly graded with the membrane potential. The key to resolving this paradox was provided by Michael Stern,whose ‘‘local control theory’’ (1) posits that CaV1.2 and RyR are clustered into spatially separated units called ‘‘couplons’’ and each couplon,