Molecular characterization of a third member of the guanylyl cyclase-activating protein subfamily

The mammalian retina contains at least two guanylyl cyclases (GC1 and GC2) and two guanylyl cyclase-activating proteins (GCAP1 and GCAP2). Here we pre sent evidence of the presence of a new photoreceptor-specific GCAP, termed GCAP3, which is closely related to GCAP1. The sequence similarity of GCAP3 with GCAP1 and GCAP2 is 57 and 49%, respectively. Recombinant GCAP3 and GCA P2 stimulate GC1 and GC2 in low [Ca2+](free) and inhibit GCs when [Ca2+](fr ee) is elevated, unlike GCAP1, which only stimulates GC1. GCAP3 is encoded by a distinct gene present in other mammalian species but could not be dete cted by genomic Southern blotting in rodents, amphibians, and lower vertebr ates. The intron/exon arrangement of the GCAP3 gene is identical to that of the other GCAP genes. While the GCAP1 and GCAP2 genes are arranged in a ta il-to-tail array on chromosome 6p in human, the GCAP3 gene is located on 3q 13.1, suggesting an ancestral gene duplication/translocation event. The ide ntification of multiple Ca2+-binding proteins that interact with GC is sugg estive of complex regulatory mechanisms for photoreceptor GC.