Antithetical modes of and the Ca(2+) sensors targeting in ANF-RGC and ROS-GC1 membrane guanylate cyclases

The membrane guanylate cyclase family has been branched into three subfamilies: natriuretic peptide hormone surface receptors, Ca(2+)-modulated neuronal ROS-GC, and Ca(2+)-modulated odorant surface receptor ONE-GC. The first subfamily is solely modulated by the extracellularly generated hormonal signals; the second, by the intracellularly generated sensory and sensory-linked signals; and the third, by combination of these two. The present study defines a new paradigm and a new mechanism of Ca(2+) signaling. (1) It demonstrates for the first time that ANF-RGC, the prototype member of the surface receptor subfamily, is stimulated by free [Ca(2+)](i). The stimulation occurs via myristoylated form of neurocalcin δ, and both the guanylate cyclase and the calcium sensor neurocalcin δ are present in the glomerulosa region of the adrenal gland. (2) The EF-2, EF-3 and EF-4 hands of GCAP1 sense the progressive increment of [Ca(2+)](i) and with a K(1/2) of 100 nM turn ROS-GC1 “OFF.” In total reversal, the same EF hands upon sensing the progressive increment of [Ca(2+)](i) with K(1/2) turn ONE-GC “ON.” The findings suggest a universal Ca(2+)-modulated signal transduction theme of the membrane guanylate cyclase family; demonstrate that signaling of ANF-RGC occurs by the peptide hormones and also by [Ca(2+)](i) signals; that for the Ca(2+) signal transduction, ANF-RGC functions as a two-component transduction system consisting of the Ca(2+) sensor neurocalcin δ and the transducer ANF-RGC; and that the neurocalcin δ in this case expands beyond its NCS family. Furthermore, the study shows a novel mechanism of the [Ca(2+)](i) sensor GCAP1 where it acts as an antithetical NCS for the signaling mechanisms of ROS-GC1 and ONE-GC.