Disease relevance of GUCA1A

• Lentivirus vectors carrying GCAP1 promoter-nlacZ transgenes were used to examine the cell specificities and temporal expression characteristics of selected promoter fragments in developing retina [1].

Psychiatry related information on GUCA1A

• A permanent ROS-GC1/GCAP-1 complex is physiologically significant, since it allows a very short response time of cyclase activity when the intracellular Ca2+-concentration changes [2].

High impact information on GUCA1A

• We show that the GCAP1(Y99C) mutant and native GCAP1 are highly effective in stimulation of photoreceptor GC1 [3].
• GCAP1 stimulates photoreceptor guanylate cyclase (GC) in bleached vertebrate photoreceptors when [Ca2+]free decreases but is inactivated when cytoplasmic [Ca2+]free increase after dark adaptation [3].
• Mutations in the gene for guanylate cyclase-activating protein-1 (GCAP1) (GUCA1A) have been associated with autosomal dominant cone dystrophy (COD3) [4].
• In the present study, a severe disease phenotype in a large white family was initially shown to map to chromosome 6p21.1, the location of GUCA1A [4].
• This represents the first disease-associated mutation in GCAP1, or any neuron-specific calcium-binding protein within an EF-hand domain, that directly coordinates Ca2+ [4].

Biological context of GUCA1A

• CONCLUSIONS: The phenotype associated with the Y99C mutation in GUCA1A is distinctive, with little variation in expression [5].
• The 4 coding exons of GUCA1A were screened for mutations in affected and unaffected family members [6].
• The guanylate cyclase activator proteins (GCAP1 and GCAP2) are calcium binding proteins which by activating Ret-GC1 play a key role in the recovery phase of phototransduction [7].
• Five point mutations in the closely related GCAP1 have been linked to the etiology of cone dystrophies [8].
• The results show that the introns of the GCAP2 gene are positioned exactly as in the GCAP1 gene and are nearly double in size [9].

Anatomical context of GUCA1A

• We suggest that the gain-of-function effects of R838C on RetGC-1 stimulated by GCAP-1, which are dominant in vitro and may cause an abnormal increase in cGMP synthesis in dark-adapted photoreceptors, may be the cause of the cone-rod degeneration [10].
• Guanylate cyclase-activating proteins (GCAP1 and GCAP2) are thought to mediate the intracellular stimulation of guanylate cyclase (GC) by Ca2+, a key event in recovery of the dark state of rod photoreceptors after exposure to light [11].
• By using a GCAP2-specific antibody in enzymatic assays, we confirmed that GCAP1 but not GCAP2 is the major component that stimulates GC in bovine rod outer segment homogenates [11].
• The expression of GCAP1 and S100B in spermatocytes and spermatids is mutually exclusive [12].
• Other significantly upregulated mRNAs included chicken ovalbumin upstream promoter-transcription factor (COUP-TF1), retinoid X receptor (RXR)-gamma, thyroid hormone receptor (TR)-beta2, and guanylyl cyclase-activating protein (GCAP)-1 [13].

Associations of GUCA1A with chemical compounds

• GCAP1 and GCAP2 are related Ca(2+)-binding proteins that activate photoreceptor guanylate cyclase(s) [9].
• 1. It was screened for mutations, and all affected individuals showed a single base pair missense mutation (A-->G) at codon 99 in exon 2 of this gene generating a tyrosine-to-cysteine change in the GCAP1 protein [14].
• In the absence of Ca(2+) GCAP stimulates and in the presence of Ca(2+) it inhibits cyclase activity [15].
• However, the response of the individual pinealocyte neuron to the norepinephrine signal depends on whether the GCAP1-linked (results in hyperpolarization) or S100beta-linked (results in depolarization) pathway is operational in the pinealocyte [16].

Physical interactions of GUCA1A

• Our results strongly indicate that evolutionary conserved and GCAP-specific amino acid residues within the EF-1 can create a contact surface for binding GCAP-2 to the cyclase [17].

Regulatory relationships of GUCA1A

• Recombinant Fugu GCAP1 failed to activate human retinal guanylate cyclase (retGC) in vitro although CD spectroscopy shows that the protein is folded with a similar secondary structure to that of human GCAP1 [18].

Other interactions of GUCA1A

• Mutation in the gene GUCA1A, encoding guanylate cyclase-activating protein 1, causes cone, cone-rod, and macular dystrophy [6].
• The intron/exon arrangement of the GCAP3 gene is identical to that of the other GCAP genes [19].
• Two of the proteins involved in this process are the enzyme, retinal guanylate cyclase (retGC), and its activating protein (GCAP) through which activity is regulated via changes in cellular Ca2+ levels [20].
• Recoverin-like proteins, GCAP-1 and GCAP-2, interact with the intracellular portion of the cyclases and stimulate its activity through dimerization of the cyclase subunits [21].

Analytical, diagnostic and therapeutic context of GUCA1A

• The GCAP1 and GCAP2 genes are transcribed into single mRNA species (1.7 and 2.2 kb, respectively) and are detectable only in the retina by Northern blotting [9].

References