S100B Serves as a Ca²⁺Sensor for ROS-GC1 Guanylate Cyclase in Cones but not in Rods of the Murine Retina

Abstract

Rod outer segment membrane guanylate cyclase (ROS-GC1) is a bimodal Ca²⁺ signal transduction switch. Lowering [Ca²⁺]_i from 200 to 20 nM progressively turns it “ON” as does raising [Ca²⁺]_i from 500 to 5000 nM. The mode operating at lower [Ca²⁺]_i plays a vital role in phototransduction in both rods and cones. The physiological function of the mode operating at elevated [Ca²⁺]_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 Ca²⁺-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 Ca²⁺ 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 [Ca²⁺]_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 [Ca²⁺]_i in cone outer segments. The findings define a new cone-specific Ca²⁺-dependent feature of photoreceptors and expand our understanding of the operational principles of phototransduction machinery.

Bicarbonate Modulates Photoreceptor Guanylate Cyclase (ROS-GC) Catalytic Activity

“…In mammalian photoreceptors ROS-GC1 is the predominant guanylate cyclase, constituting ϳ80% in WT mouse rod outer segments (32) and more than 90% in those of bovine (33). In the all-cone retina of mutant Nrl Ϫ/Ϫ mouse, ROS-GC1 is expressed almost exclusively and is bound to GCAP1 (20) and another Ca 2ϩ sensor, S100B (15). The shift in ED 50 to higher bicarbonate concentrations in ROS-GC activity from WT mouse compared with that from Nrl Ϫ/Ϫ mouse (Fig.…”

“…15 were assayed using methods similar to that for COS cell membranes except that 10 M zaprinast was added to inhibit endogenous PDE6 activity. Assays were performed three times, each time in triplicate.…”

Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate

“…The first two pathways are specific for rod photoreceptors (Makino et al, 2008, 2012; Koch and Dell’orco, 2013); GCAP1- and S100B-modulated for the cone photoreceptors (Wen et al, 2012; Sharma et al, 2014) and the GCAP1 and CO 2 /bicarbonate-modulated pathways for the red cone photoreceptors (Duda et al, 2015). Notably, the migratory patterns of these pathways are very different, yet they all are translated to generate cyclic GMP at a common CCD center.…”

Differential Ca2+ Sensor Guanylate Cyclase Activating Protein Modes of Photoreceptor Rod Outer Segment Membrane Guanylate Cyclase Signaling

“…12 of reference 7). The presence and functional linkage of ROS-GC1 with Ca 2+ -sensor, S100B, has been mapped in the cone outer segments of the mouse retina 7 . Intriguingly, this pathway is not present in the mouse rods.…”