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© The Rockefeller University Press, 0021-9525/1997//351 $5.00
The Journal of Cell Biology, Volume 139, Number 2, , 1997 351-363

The Phosphatidylinositol Transfer Protein Domain of Drosophila Retinal Degeneration B Protein Is Essential for Photoreceptor Cell Survival and Recovery from Light Stimulation

Scott C. Milligan^*, James G. Alb, Jr., Raya B. Elagina^*, Vytas A. Bankaitis, and David R. Hyde^*

^* Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556; and Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294

The Drosophila retinal degeneration B (rdgB) gene encodes an integral membrane protein involved in phototransduction and prevention of retinal degeneration. RdgB represents a nonclassical phosphatidylinositol transfer protein (PITP) as all other known PITPs are soluble polypeptides. Our data demonstrate roles for RdgB in proper termination of the phototransduction light response and dark recovery of the photoreceptor cells. Expression of RdgB's PITP domain as a soluble protein (RdgB-PITP) in rdgB² mutant flies is sufficient to completely restore the wild-type electrophysiological light response and prevent the degeneration. However, introduction of the T59E mutation, which does not affect RdgB-PITP's phosphatidylinositol (PI) and phosphatidycholine (PC) transfer in vitro, into the soluble (RdgB-PITP-T59E) or full-length (RdgB-T59E) proteins eliminated rescue of retinal degeneration in rdgB² flies, while the light response was partially maintained. Substitution of the rat brain PITP, a classical PI transfer protein, for RdgB's PITP domain (PITP or PITP-RdgB chimeric protein) neither restored the light response nor maintained retinal integrity when expressed in rdgB² flies. Therefore, the complete repertoire of essential RdgB functions resides in RdgB's PITP domain, but other PITPs possessing PI and/or PC transfer activity in vitro cannot supplant RdgB function in vivo. Expression of either RdgB-T59E or PITP-RdgB in rdgB⁺ flies produced a dominant retinal degeneration phenotype. Whereas RdgB-T59E functioned in a dominant manner to significantly reduce steady-state levels of rhodopsin, PITP-RdgB was defective in the ability to recover from prolonged light stimulation and caused photoreceptor degeneration through an unknown mechanism. This in vivo analysis of PITP function in a metazoan system provides further insights into the links between PITP dysfunction and an inherited disease in a higher eukaryote.

Abbreviations used in this paper: ERG, electroretinogram; PC, phosphatidychloine; PDA, prolonged depolarizing afterpotential(s); PI, phosphatidylinositol; PITP, phosphatidylinositol transfer protein; PLC, phospholipase C; PKC, protein kinase C; rdgB, retinal degeneration B; RdgB, retinal degeneration B protein; RdgB-PITP, RdgB PITP domain; SM, sphingomyelin.

Address all correspondence to David R. Hyde, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 45665. Tel.: (219) 631-8054. Fax: (219) 631-7413. E-mail: david.r.hyde.1{at}nd.edu

Received for publication 10 March 1997 and in revised form 15 July 1997.

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