Journal article
Protein inhibitor of retinal membrane guanylyl cyclase suppresses cGMP synthesis in photoreceptors
The Journal of biological chemistry, v 301(10), 110718
01 Oct 2025
PMID: 40962054
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Retinal membrane guanylyl cyclase (RetGC) regulated by RetGC activating proteins (GCAPs) imparts light sensitivity to rods and cones by producing cyclic GMP (cGMP) to open cGMP-gated channels in the photoreceptor outer segments. However, excessive cGMP synthesis by deregulated RetGC:GCAP complex provokes cone-rod degeneration and causes congenital blindness. We developed the first to date specific protein inhibitor of retinal guanylyl cyclase (PIGCY) capable of reducing RetGC activity in photoreceptor outer segment. PIGCY was constructed by modifying GCAP1 to eliminate its ability to activate RetGC while increasing its affinity for RetGC. PIGCY uncouples RetGC1:GCAP1 complex in vitro, reducing Vmax and increasing KmGTP of RetGC activity. PIGCY inhibits both basal and GCAP-stimulated RetGC activity from wildtype, GCAP1−/−, GCAP2−/−, and GCAPs−/− mouse retinas homogenates and in isolated rod outer segments. When expressed in mouse rods, PIGCY accumulates in outer segments and decelerates endogenous GCAP-stimulated RetGC activity in PIGCYTg retina.
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Details
- Title
- Protein inhibitor of retinal membrane guanylyl cyclase suppresses cGMP synthesis in photoreceptors
- Creators
- Igor V. Peshenko - Drexel University, Pennsylvania College of Optometry (PCO)Elena V. Olshevskaya - Drexel University, Pennsylvania College of Optometry (PCO)Alexander M. Dizhoor - Drexel University, Neurobiology and Anatomy
- Publication Details
- The Journal of biological chemistry, v 301(10), 110718
- Publisher
- Elsevier Inc
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:001600168400002
- Scopus ID
- 2-s2.0-105018583061
- Other Identifier
- 991022116333204721
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- Web of Science research areas
- Biochemistry & Molecular Biology