Neurocalcin δ modulation of ROS-GC1, a new model of Ca²⁺ signaling

ROS-GC1 membrane guanylate cyclase is a Ca²⁺ bimodal signal transduction switch. It is turned "off" by a rise in free Ca ²⁺ from nanomolar to the semicromolar range in the photoreceptor outer segments and the olfactory bulb neurons; by a similar rise in the bipolar and ganglion retinal neurons it is turned "on". These opposite operational modes of the switch are specified by its Ca²⁺ sensing devices, respectively termed GCAPs and CD-GCAPs. Neurocalcin δ is a CD-GCAP. In the present study, the neurocalcin δ-modulated site, V ⁸³⁷-L⁸⁵⁸, in ROS-GC1 has been mapped. The location and properties of this site are unique. It resides within the core domain of the catalytic module and does not require the α-helical dimerization domain structural element (amino acids 767-811) for activating the catalytic module. Contrary to the current beliefs, the catalytic module is intrinsically active; it is directly regulated by the neurocalcin δ-modulated Ca²⁺ signal and is dimeric in nature. A fold recognition based model of the catalytic domain of ROS-GC1 was built, and neurocalcin r5 docking simulations were carried out to define the three-dimensional features of the interacting domains of the two molecules. These findings define a new transduction model for the Ca²⁺ signaling of ROS-GC1.