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Abstract
The mammalian retina contains at least two guanylyl cyclases (GC1 and GC2) and two guanylyl cyclase-activating proteins (GCAP1 and GCAP2). Here we present 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 GCAP2 stimulate GC1 and GC2 in low [Ca2+]free and inhibit GCs when [Ca2+]free is elevated, unlike GCAP1, which only stimulates GC1. GCAP3 is encoded by a distinct gene present in other mammalian species but could not be detected by genomic Southern blotting in rodents, amphibians, and lower vertebrates. 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 tail-to-tail array on chromosome 6p in human, the GCAP3 gene is located on 3q13.1, suggesting an ancestral gene duplication/translocation event. The identification of multiple Ca2+-binding proteins that interact with GC is suggestive of complex regulatory mechanisms for photoreceptor GC.
Highlights
Absorption of light by rhodopsin results in a decrease of [cGMP] within photoreceptor outer segments [1]
The most intense labeling with anti-GCAP1 antibodies has been observed in cone outer segments, and weaker labeling has been observed in rod outer segments [8, 21]
Since human rods are unaffected in autosomal dominant cone dystrophy, GCAP2 or a third Guanylyl cyclase-activating proteins (GCAPs)-like Ca2ϩ-binding protein may substitute in part for the mutant GCAP1, or rods are less sensitive to elevated cGMP levels [18]
Summary
Absorption of light by rhodopsin results in a decrease of [cGMP] within photoreceptor outer segments [1]. 1 The abbreviations used are: GCAP, guanylyl cyclase-activating protivated by this decrease in [Ca2ϩ] and accelerate cGMP production by stimulating GCs. Increase in [cGMP] leads to the opening of the cation channels and restores the dark conditions of photoreceptors [5]. Since human rods are unaffected in autosomal dominant cone dystrophy, GCAP2 or a third GCAP-like Ca2ϩ-binding protein may substitute in part for the mutant GCAP1, or rods are less sensitive to elevated cGMP levels [18]. We describe molecular cloning and characterization of a third form of GCAP, GCAP3, which by sequence similarity appears to be more closely related to GCAP1 than to GCAP2 This novel isoform provides additional evidence of complex regulations of cGMP production/degradation in photoreceptor cells from different species and of the existence of an evolving family of GCAP genes
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