Sharma, Rameshwar K.Makino, Clint L.Hicks, DavidDuda, Teresa2014-05-062014Sharma, Rameshwar K., Clint L. Makino, David Hicks, and Teresa Duda. 2014. “ROS-GC interlocked Ca2+-sensor S100B protein signaling in cone photoreceptors: review.” Frontiers in Molecular Neuroscience 7 (1): 21. doi:10.3389/fnmol.2014.00021. http://dx.doi.org/10.3389/fnmol.2014.00021.1662-5099http://nrs.harvard.edu/urn-3:HUL.InstRepos:12153029Photoreceptor rod outer segment membrane guanylate cyclase (ROS-GC) is central to visual transduction; it generates cyclic GMP, the second messenger of the photon signal. Photoexcited rhodopsin initiates a biochemical cascade that leads to a drop in the intracellular level of cyclic GMP and closure of cyclic nucleotide gated ion channels. Recovery of the photoresponse requires resynthesis of cyclic GMP, typically by a pair of ROS-GCs, 1 and 2. In rods, ROS-GCs exist as complexes with guanylate cyclase activating proteins (GCAPs), which are Ca2+-sensing elements. There is a light-induced fall in intracellular Ca2+. As Ca2+ dissociates from GCAPs in the 20–200 nM range, ROS-GC activity rises to quicken the photoresponse recovery. GCAPs then progressively turn down ROS-GC activity as Ca2+ and cyclic GMP levels return to baseline. To date, GCAPs mediate the only known mechanism of ROS-GC regulation in the photoreceptors. However, in mammalian cone outer segments, cone synapses and ON bipolar cells, another Ca2+ sensor protein, S100B, complexes with ROS-GC1 and senses the Ca2+ signal with a K1/2 of 400 nM. Unlike GCAPs, S100B stimulates ROS-GC activity when Ca2+ is bound. Thus, the ROS-GC system in cones functions as a Ca2+ bimodal switch; with rising intracellular Ca2+, its activity is first turned down by GCAPs and then turned up by S100B. This presentation provides a historical perspective on the role of S100B in the photoreceptors, offers a pictorial model for the “bimodal” operation of the ROS-GC switch and projects future tasks that are needed to understand its operation. Some accounts of this review have been adopted from the original publications of these authors.en-USReview ArticleROS-GC guanylate cyclasecyclic GMPphototransductionconesS100BJournal Article2014-05-0610.3389/fnmol.2014.00021