GARP2 used in the earlier study [32]. Native GARP2 has been shown to reduce the basal activity of the dark-adapted PDE6 holoenzyme by up to 80% [177]. This result suggests that GARP2 may reinforce the inhibitory action of the γ-subunit on nonactivated PDE6, thereby enhancing the signal-to-noise ratio of rod photoreceptors under very dim (e.g., single-photon) illumination conditions.

Other roles for GARP2 have been postulated [173, 176, 178], and it remains to be determined what rod-specific role(s) GARP2 plays in regulating PDE6 or other phototransduction proteins during visual signaling.

17-kDa Prenyl-Binding Protein (PDEδ)

The 17-kDa prenyl-binding protein (PrBP/δ) was prematurely identified as the PDE6 δ-subunit because it copurified with a soluble fraction (20–30% of the total) of PDE6 from bovine retinal extracts [172, 179]. Unlike most photoreceptor proteins with tissue distribution that is restricted to the retina, PrBP/δ is ubiquitously expressed [179, 180]. PrBP/δ is capable of interacting with numerous proteins, most—but not all of which—are posttranslationally modified with farnesyl or geranylgeranyl groups (for review, see [181]).

The functions of PrBP/δ in photoreceptor cells have been addressed by subcellular localization studies that have variously observed PrBP/δ immunoreactivity in the outer segments, the inner segments, as well as the connecting cilium region between inner and outer segments of both rods and cones [179, 182–184]. Localization of PrBP/δ in the inner segment and the connecting cilium region of the photoreceptor is consistent with a role for PrBP/δ in the transport of prenylated proteins from their site of synthesis in the inner segment to the outer segment. This idea is supported by identification of PrBP/ δ-binding partners that are thought to be involved in vesicular transport [185–187]. Recent work with a transgenic mouse in which the PrBP/δ gene has been deleted shows a reduction in transport of opsin kinase (a prenylated protein) to the outer segments of rods and cones, with corresponding defects in the photoresponse [183].

Biochemical studies have shown that PrBP/δ is a high-affinity PDE6-binding protein, with specific interaction with the farnesylated and geranylgeranylated C-termini of rod PDE6 catalytic subunits. Binding of PrBP/δ with PDE6 releases PDE6 from its disk membrane attachment site [179, 184, 188]. Once solubilized, the ability of activated transducin α-subunit to activate PDE6 is greatly impaired [184, 189]. In addition, PrBP/δ binding to PDE6 reduces cGMP-binding affinity to one of the two GAF domain binding sites [96] and disrupts the high-affinity interaction of PDE6 with GARP2 [177].

These specific effects of PrBP/δ on PDE6 in vitro support a role for PrBP/δ in negativefeedback regulation of PDE6 activation, perhaps during prolonged light adaptation. However, the PrBP/δ content in rod outer segments is only 10% of the PDE6 concentration [184], arguing against PrBP/δ as a bona fide PDE6 regulatory subunit. More work is needed to fully understand the role of PrBP/δ in the phototransduction pathway or in protein transport in photoreceptor cells.

CONCLUSIONS

Considering the wealth of knowledge about the phototransduction pathway—arguably the most thoroughly characterized of the G protein-coupled signaling pathways—it is humbling to realize that major gaps remain in understanding the complexities of PDE6

regulation at the center of the cGMP signaling cascade. The detailed sequence of events leading to transducin activation of the PDE6 holoenzyme remains to be determined. The physiological significance of the allosteric communication of the PDE6 GAF domains through the inhibitory γ-subunit remains speculative at present. Some aspects of the complex set of processes known as “light adaptation” are postulated to operate by novel mechanisms [190–192]. Novel PDE6 regulatory proteins are possible candidates to modulate PDE6 activity during light adaptation. Finally, this review focused almost exclusively on visual transduction in rod photoreceptors, in large part because so little is known about the extent to which differences between rod and cone PDE6 regulation may account for some of the physiological differences in rod and cone photoresponses [193].

PDE6 is coming under increasing scrutiny outside of the field of vision research. With the increasing reliance on PDE inhibitors for a growing number of therapeutic applications (e.g., male erectile dysfunction, pulmonary hypertension), potential adverse effects on PDE6 function must be considered. There is also limited evidence to date that PDE6 subunits may be found outside the retina and may be differentially expressed during development. Having a G protein-coupled PDE6 expressed in nonphotoreceptive cells is extremely intriguing and merits further investigation of how PDE6 may participate in regulating cyclic nucleotide levels in other cells and tissues.

ACKNOWLEDGMENTS

Work from my laboratory is supported by the National Eye Institute (EY05798). This is Scientific Contribution 2313 from the New Hampshire Agricultural Experiment Station.

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