Journal article
Enzymatic Relay Mechanism Stimulates Cyclic GMP Synthesis in Rod Photoresponse: Biochemical and Physiological Study in Guanylyl Cyclase Activating Protein 1 Knockout Mice
PloS one, v 7(10), 47637
17 Oct 2012
PMID: 23082185
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Regulation of cGMP synthesis by retinal membrane guanylyl cyclase isozymes (RetGC1 and RetGC2) in rod and cone photoreceptors by calcium-sensitive guanylyl cyclase activating proteins (GCAP1 and GCAP2) is one of the key molecular mechanisms affecting the response to light and is involved in congenital retinal diseases. The objective of this study was to identify the physiological sequence of events underlying RetGC activation in vivo, by studying the electrophysiological and biochemical properties of mouse rods in a new genetic model lacking GCAP1. The GCAP1(-/-) retinas expressed normal levels of RetGC isozymes and other phototransduction proteins, with the exception of GCAP2, whose expression was elevated in a compensatory fashion. RetGC activity in GCAP1(-/-) retinas became more sensitive to Ca2+ and slightly increased. The bright flash response in electroretinogram (ERG) recordings recovered quickly in GCAP1(-/-), as well as in RetGC1(-/-) GCAP1(-/-), and RetGC2(-/-) GCAP1(-/-) hybrid rods, indicating that GCAP2 activates both RetGC isozymes in vivo. Individual GCAP1(-/-) rod responses varied in size and shape, likely reflecting variable endogenous GCAP2 levels between different cells, but single-photon response (SPR) amplitude and time-to-peak were typically increased, while recovery kinetics remained faster than in wild type. Recovery from bright flashes in GCAP1(-/-) was prominently biphasic, because rare, aberrant SPRs producing the slower tail component were magnified. These data provide strong physiological evidence that rod photoresponse recovery is shaped by the sequential recruitment of RetGC isozyme activation by GCAPs according to the different GCAP sensitivities for Ca2+ and specificities toward RetGC isozymes. GCAP1 is the 'first-response' sensor protein that stimulates RetGC1 early in the response and thus limits the SPR amplitude, followed by activation of GCAP2 that adds stimulation of both RetGC1 and RetGC2 to speed-up photoreceptor recovery.
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Details
- Title
- Enzymatic Relay Mechanism Stimulates Cyclic GMP Synthesis in Rod Photoresponse: Biochemical and Physiological Study in Guanylyl Cyclase Activating Protein 1 Knockout Mice
- Creators
- Clint L. Makino - Harvard UniversityXiao-Hong Wen - Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USAElena V. Olshevskaya - Salus UniversityIgor V. Peshenko - Salus UniversityAndrey B. Savchenko - Salus UniversityAlexander M. Dizhoor - Salus University
- Publication Details
- PloS one, v 7(10), 47637
- Publisher
- Public Library of Science
- Number of pages
- 12
- Grant note
- Pennsylvania Department of Health Formula Grant Lion's of Massachusetts EY11522; EY011358; EY014104 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R29EY011358 / NATIONAL EYE INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:000311146900081
- Scopus ID
- 2-s2.0-84867656888
- Other Identifier
- 991022035261904721
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- Web of Science research areas
- Biochemistry & Molecular Biology