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Alex S. McKeown, Shanta S. Sarfare, Steven J. Pittler, Timothy W. Kraft; Phototransduction Gain Is Increased In Rods Overexpressing GARP2. Invest. Ophthalmol. Vis. Sci. 2012;53(14):755.
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GARP2, a soluble glutamic acid and proline rich photoreceptor-specific protein has been linked to rod structure and disk morphogenesis. The protein is also known to associate with PDE6 (Pentia et al., 2006) and as such could have a physiological role. We previously showed using ERG analysis that transgenic mice over-expressing GARP2 by two-fold (GARP2 Tg) exhibit phototransduction gain 50-80% higher than that of wild-type animals. Here we compare the in vivo ERG results with alternative techniques that more specifically isolated rod photoreceptor electrical responses which provide strong supporting evidence for a role of GARP2 in phototransduction.
Isolated photoreceptor currents and voltages were recorded from retinas or single cells of wild type and GARP2-Tg animals. Light stimuli varied from intensities that evoked minimum threshold responses up to those producing saturating responses. En masse recordings from a population of photoreceptors (ex-vivo ERG) were conducted by pharmacologically isolating the a-wave in the isolated retina. Single cell recordings were made using suction electrodes.
In both preparations, the rising phase of the responses were analyzed using a rod model of gain (Lamb & Pugh, 1992). Both the isolated retina preparation (n=2 WT; n=3 GARP-Tg) and single cell photoreceptors (n=7 WT; n=4 GARP2 Tg) demonstrated significantly higher gain in the GARP2 Tg mice. While the single cell results were more modest (25% gain increase) the GARP2 Tg isolated retinas showed a 3-fold increase in gain. The dominant time constant of the photoresponse recovery, a measure of PDE6 inactivation rate, was also significantly increased in the transgenic animals.
Two-fold overexpression of GARP2 increases phototransduction gain, and delays recovery by increasing the dominant time constant. One plausible explanation is that an abundance of GARP2, through interactions with PDE6-gamma facilitates binding of T-αGTP, increasing gain, and inhibiting interactions of the RGS9 complex with activated PDE6. Our results indicate a role for GARP2 in modulating phototransduction.
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