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by claude@2026-06, 2026-06-24
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The study investigated the molecular mechanism underlying human cone outer segment optoretinography responses, focusing on how light-evoked shrinkage and subsequent elongation are regulated in relation to G-protein signaling. Researchers used human subjects with bradyopsia caused by a triple-deletion mutation in R9AP, assessed outer segment responses, and performed immunoprecipitation to show reduced binding between mutant R9AP and RGS9, leading to diminished RGS9 levels. They found that cone elongation activation kinetics, amplitude, and photosensitivity were normal, but recovery was markedly slowed, indicating that normal RGS9 is required for deactivation of the elongation response within the G-protein cascade or the GAP complex. Using paired-flash paradigms, they further showed elongation depends on a GDP-bound transducin complex substrate depleted by high bleaches and recovering in bleach-dependent fashion, though the preprint does not provide additional limitations beyond the described findings. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
ABSTRACT Human cone and rod outer segments exhibit a rapid shrinkage followed by a slower elongation in response to light, forming the basis of the optoretinogram. The molecular basis of this optical assay of photoreceptor function remains incompletely understood. In mouse rods, the elongation response requires transducin, the G-protein α-subunit activated in the initial amplifying step of the phototransduction cascade. Here, we measured human cone outer segment responses in subjects with bradyopsia arising from a triple-deletion mutation in R9AP, the anchor and transport protein for the GTPase-activating protein (GAP) RGS9. Immunoprecipitation showed that the mutant R9AP has greatly reduced affinity for RGS9, predictably reducing the level of RGS9 in the outer segment. The bradyopsia subjects’ elongation responses had normal activation kinetics, amplitude and photosensitivity, but markedly slowed recovery. These results indicate that normal levels of RGS9 are required for deactivation of the cone elongation response, situating the underlying molecular mechanism within the G-protein cascade at or prior to formation of the GAP complex. The recovery of the cone elongation response, measured in a paired-flash paradigm for stimuli isomerizing up to 75% of opsin, revealed that elongation requires a substrate that is depleted and recovers in a bleach-dependent manner. In particular, recovery from the highest bleaching exposure (75%) tracked the time course of cone opsin regeneration, implying that unregenerated cone opsin produces “ dark light ”, known in rods to arise from constitutive activation of G-protein. Taken together, the results from controls and bradyopsia identify the inactive (GDP-bound) transducin complex as the essential substrate for the human cone elongation response. Suppression of the elongation response in the paired-flash paradigm further revealed the complete profile of the initial fast cone outer segment shrinkage response and reinforced its origin in opsin structural changes. Overall, these results identify key mechanistic elements of the optoretinogram and enable its use as a molecularly interpretable, non- invasive assay of cone function in disease and therapeutic response.
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Abstract
Human cone and rod outer segments exhibit a rapid shrinkage followed by a slower elongation in response to light, forming the basis of the optoretinogram. The molecular basis of this optical assay of photoreceptor function remains incompletely understood. In mouse rods, the elongation response requires transducin, the G-protein α-subunit activated in the initial amplifying step of the phototransduction cascade. Here, we measured human cone outer segment responses in subjects with bradyopsia arising from a triple-deletion mutation in R9AP, the anchor and transport protein for the GTPase-activating protein (GAP) RGS9. Immunoprecipitation showed that the mutant R9AP has greatly reduced affinity for RGS9, predictably reducing the level of RGS9 in the outer segment. The bradyopsia subjects' elongation responses had normal activation kinetics, amplitude and photosensitivity, but markedly slowed recovery. These results indicate that normal levels of RGS9 are required for deactivation of the cone elongation response, situating the underlying molecular mechanism within the G-protein cascade at or prior to formation of the GAP complex. The recovery of the cone elongation response, measured in a paired-flash paradigm for stimuli isomerizing up to 75% of opsin, revealed that elongation requires a substrate that is depleted and recovers in a bleach-dependent manner. In particular, recovery from the highest bleaching exposure (75%) tracked the time course of cone opsin regeneration, implying that unregenerated cone opsin produces " dark light ", known in rods to arise from constitutive activation of G-protein. Taken together, the results from controls and bradyopsia identify the inactive (GDP-bound) transducin complex as the essential substrate for the human cone elongation response. Suppression of the elongation response in the paired-flash paradigm further revealed the complete profile of the initial fast cone outer segment shrinkage response and reinforced its origin in opsin structural changes. Overall, these results identify key mechanistic elements of the optoretinogram and enable its use as a molecularly interpretable, non-invasive assay of cone function in disease and therapeutic response.
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