Rod outer segment membrane guanylate cyclase (ROS-GC1) is a bimodal Ca 2+ signal transduction switch. Lowering [Ca 2+ ] i from 200 to 20 nM progressively turns it "ON" as does raising [Ca 2+ ] i from 500 to 5000 nM. The mode operating at lower [Ca 2+ ] i plays a vital role in phototransduction in both rods and cones. The physiological function of the mode operating at elevated [Ca 2+ ] i is not known. Through comprehensive studies on mice involving gene deletions, biochemistry, immunohistochemistry, electroretinograms and single cell recordings, the present study demonstrates that the Ca 2+ -sensor S100B coexists with and is physiologically linked to ROS-GC1 in cones but not in rods. It up-regulates ROS-GC1 activity with a K 1/2 for Ca 2+ greater than 500 nM and modulates the transmission of neural signals to cone ON-bipolar cells. Furthermore, a possibility is raised that under pathological conditions where [Ca 2+ ] i levels rise to and perhaps even enter the micromolar range, the S100B signaling switch will be turned "ON" causing an explosive production of CNG channel opening and further rise in [Ca 2+ ] i in cone outer segments. The findings define a new cone-specific Ca 2+ -dependent feature of photoreceptors and expand our understanding of the operational principles of phototransduction machinery.
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