GCAP1 (Y99C) mutant is constitutively active in autosomal dominant cone dystrophy.
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. A Y99C mutation in GCAP1 has recently been found to be associated with autosomal dominant cone dystrophy. We show that the GCAP1(Y99C) mutant and native GCAP1 are highly effective in stimulation of photoreceptor GC1. The Ca2+ sensitivity of the mutant GCAP1, however, is markedly altered, causing reduced but persistent stimulation of GC1 under physiological dark conditions. These results are consistent with a model in which enhanced GC activity in dark-adapted cones leads to elevated levels of cytoplasmic cGMP. Alterations in physiological cGMP levels are also associated with other retinal degenerations, including Leber's congenital amaurosis.
Sokal
I
I
Department of Ophthalmology, School of Medicine, University of Washington, Seattle 98195, USA.
Li
N
N
Surgucheva
I
I
Warren
M J
MJ
Payne
A M
AM
Bhattacharya
S S
SS
Baehr
W
W
Palczewski
K
K
D000222:Adaptation, Physiological; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D002417:Cattle; D002460:Cell Line; D003001:Cloning, Molecular; D003117:Color Vision Defects / Q000235:genetics* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003624:Darkness; D004789:Enzyme Activation; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000378:metabolism; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D005799:Genes, Dominant; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism; D051604:Guanylate Cyclase-Activating Proteins; D006801:Humans; D008268:Macular Degeneration; D009036:Moths; D016297:Mutagenesis, Site-Directed; D015418:Optic Atrophies, Hereditary / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
D002135:Calcium-Binding Proteins; D005136:Eye Proteins; C496736:GUCA1A protein, human; D051604:Guanylate Cyclase-Activating Proteins; D011993:Recombinant Fusion Proteins; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium