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Correspondence to Edward N. Pugh Jr.: pugh{at}mail.med.upenn.edu
The retinas of mice null for the neural retina leucine zipper transcription factor (Nrl –/–) contain no rods but are populated instead with photoreceptors that on ultrastructural, histochemical, and molecular criteria appear cone like. To characterize these photoreceptors functionally, responses of single photoreceptors of Nrl –/– mice were recorded with suction pipettes at 35–37°C and compared with the responses of rods of WT mice. Recordings were made either in the conventional manner, with the outer segment (OS) drawn into the pipette ("OS in"), or in a novel configuration with a portion of the inner segment drawn in ("OS out"). Nrl –/– photoreceptor responses recorded in the OS-out configuration were much faster than those of WT rods: for dim-flash responses tpeak = 91 ms vs. 215 ms; for saturating flashes, dominant recovery time constants, 
D = 110 ms vs. 240 ms, respectively. Nrl –/– photoreceptors in the OS-in configuration had reduced amplification, sensitivity, and slowed recovery kinetics, but the recording configuration had no effect on rod response properties, suggesting Nrl –/– outer segments to be more susceptible to damage. Functional coexpression of two cone pigments in a single mammalian photoreceptor was established for the first time; the responses of every Nrl –/– cell were driven by both the short-wave (S, 
max 
360 nm) and the mid-wave (M, max 510 nm) mouse cone pigment; the apparent ratio of coexpressed M-pigment varied from 1:1 to 1:3,000 in a manner reflecting a dorso-ventral retinal position gradient. The role of the G-protein receptor kinase Grk1 in cone pigment inactivation was investigated in recordings from Nrl –/–/Grk1–/– photoreceptors. Dim-flash responses of cells driven by either the S- or the M-cone pigment were slowed 2.8-fold and 7.5-fold, respectively, in the absence of Grk1; the inactivation of the M-pigment response was much more seriously retarded. Thus, Grk1 is essential to normal inactivation of both S- and M-mouse cone opsins, but S-opsin has access to a relatively effective, Grk1-independent inactivation pathway.
Key Words: phototransduction • GPCR signaling • cone opsin • Grk1 • spectral sensitivity
Abbreviations used in this article: OS, outer segment; WT, wild-type.
1 The mouse genome contains the genes of two cone pigments, one from the shortwave sensitive class 1 (SWS1) homology group having
max = 359 nm (Yokoyama et al., 1998), and a second from the long/midwave sensitive homology group (MWS/LWS) with max = 508 nm (Sun et al., 1997). The SWS1 group has maxs ranging from 358 to 425 nm and includes the human S-cone pigment, while the MWS/LWS group has maxs ranging from 508 to 611 nm and includes both the human M-cone and L-cone pigments (Yokoyama and Yokoyama, 2000; Ebrey and Koutalos, 2001). To reflect their homology group memberships, in this manuscript we will often refer to the mouse cone pigments with the generic labels "S-cone pigment" and "M-cone pigment." At other times, when the ultraviolet sensitivity of the mouse S-pigment is at issue, we will use the terminology "UV-cone pigment" to denote the mouse cone pigment with max = 359 nm.
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