Arrestins have been implicated in the regulation of many G protein-coupled receptor signaling cascades. Mutations in two Drosophila photoreceptor-specific arrestin genes, arrestin 1 and arrestin 2, were generated. Analysis of the light response in these mutants shows that the Arr1 and Arr2 proteins are mediators of rhodopsin inactivation and are essential for the termination of the phototransduction cascade in vivo. The saturation of arrestin function by an excess of activated rhodopsin is responsible for a continuously activated state of the photoreceptors known as the prolonged depolarized afterpotential. In the absence of arrestins, photoreceptors undergo light-dependent retinal degeneration as a result of the continued activity of the phototransduction cascade. These results demonstrate the fundamental requirement for members of the arrestin protein family in the regulation of G protein-coupled receptors and signaling cascades in vivo (Dolph, 1993).
Mutations in proteins of the Drosophila phototransduction cascade, a prototypic guanine nucleotide-binding protein-coupled receptor signaling system, lead to retinal degeneration and have been used as models to understand human degenerative disorders. In this study, modulating the sphingolipid biosynthetic pathway rescued retinal degeneration in Drosophila mutants. Targeted expression of Drosophila neutral ceramidase rescues retinal degeneration in arrestin and phospholipase C mutants. Decreasing flux through the de novo sphingolipid biosynthetic pathway also suppresses degeneration in these mutants. Both genetic backgrounds modulate the endocytic machinery because they suppressed defects in a dynamin mutant. Suppression of degeneration in arrestin mutant flies expressing ceramidase correlates with a decrease in ceramide levels. Thus, enzymes of sphingolipid metabolism may be suitable targets in the therapeutic management of retinal degeneration (Acharya, 2003).
Sphingolipids are integral components of eukaryotic cell membranes and also a rich source of second messengers for several signal transduction cascades. Sphingolipid metabolism generates and interconverts various metabolites including ceramide, sphingosine, and sphingosine 1-phosphate, which are second messengers in diverse signaling pathways that affect cell cycle, apoptosis, and angiogenesis, among others. Serine palmitoyl-CoA transferase (SPT) catalyzes the rate-limiting first step in the de novo biosynthesis of sphingolipids including ceramide. Ceramidases hydrolyze ceramide to sphingosine, and neutral or alkaline ceramidase is proposed to function in signaling. Mutant analyses in yeast have implicated enzymes of sphingolipid metabolism in endocytic membrane trafficking events. This study modulated the sphingolipid biosynthetic pathway in vivo in Drosophila and examined its effects on mutants with endocytic defects in photoreceptors (Acharya, 2003).
Each of the 800 ommatidia of a Drosophila compound eye consists of eight photoreceptor cells (R1 to R8). Each cell has a rhabdomere, a specialized microvillar structure derived from the plasma membrane that houses the phototransduction machinery. Rhabdomere architecture is sensitive to perturbations in the phototransduction cascade and has been used to monitor photoreceptor degeneration. Drosophila phototransduction is a prototypic GTP-binding protein-coupled receptor (GPCR) cascade that is initiated by light activation of rhodopsin. Association of arrestin 2 with phosphorylated rhodopsin leads to deactivation of rhodopsin. Drosophila arrestin 2 also acts as a clathrin adaptor, mediating endocytosis of arrestin-rhodopsin complexes. arr23 mutants (Val52 to Asp) make less than 1% of the protein, are defective in endocytosis, accumulate abnormal multivesicular bodies, show extensive retinal degeneration, and undergo necrotic cell death. These changes also result in a precipitous drop in rhodopsin levels in these photoreceptors. Thus, arr23 photoreceptors provide a sensitive background for examining the in vivo effects of modulating the sphingolipid pathway in endocytosis (Acharya, 2003).
The ceramidase gene was cloned into an UAS vector, and it was expressed in the Drosophila eye with the use of a glass multimer reporter (GMR)-Gal4 driver. Extracts from these fly heads showed increased neutral ceramidase activity, confirming that the protein was a bona fide neutral ceramidase. Expression of GMR-Gal4; UAS-ceramidase in R1 to R6 did not affect photoreceptor integrity. Expression of ceramidase in arr23 rescued photoreceptor degeneration. In transmission electron micrographs (TEMs), rhabdomeres were intact, and multivacuolar bodies and degenerating photoreceptors, characteristic of arr23 mutants, were completely absent in a 3-day arr23 fly expressing ceramidase. A near-wild-type level of rhodopsin was seen in rescued flies, reflecting photoreceptor integrity. Thus, expression of ceramidase in arr23 preserved rhabdomere structure and organization. Although defective, newly eclosed arr23 flies transduce light signals. As they age, they undergo progressive degeneration and lose their ability to transmit signals. To test whether rescued flies retain their functional ability to signal, electroretinogram recordings (ERG) were carried out from 7-day-old flies exposed to light. Because of extensive degeneration, ERGs of arr23 flies had a very small amplitude, whereas arr23 flies expressing ceramidase showed a robust response. However, the slow inactivation kinetics characteristic of arr23 still persisted in the rescued flies. Rescued arrestin mutant flies transduced signals even on aging because the structural integrity of these photoreceptors was preserved (Acharya, 2003).
Because expression of ceramidase in arrestin mutant flies suppressed retinal degeneration and because ceramidase hydrolyzed ceramide, it was reasoned that the rescue would be accompanied by a decrease in ceramide levels in these photoreceptors. Electrospray ionization tandem mass spectrometry (ESI/MS/MS) was used to estimate ceramide levels in lipid extracts of membranes prepared from fly heads of control, ceramidase expressor, arrestin mutant, and arrestin mutant expressing ceramidase. Ceramide molecular species containing tetradecasphingenine and their 2-hydroxy counterparts were identified by negative ion ESI/MS/MS with neutral loss of 200.2 and 271.2 mass units, respectively. As expected, expression of ceramidase reduces the ceramide levels in control animals. Lipid extracts from arrestin mutants showed an increase in ceramide levels, probably reflecting changes accompanying the severely degenerating photoreceptors. Expression of ceramidase in arrestin mutants decreased ceramide levels by 50% in all species measured. Thus, rescue of degeneration correlated with a decrease in ceramide levels in the mutant flies. Because sphingosine is a product of the ceramidase reaction, whether increased sphingosine could suppress retinal degeneration in arrestin mutants was evaluated. Viability of certain lace alleles (LCB2 subunit of SPT, a.k.a. Serine palmitoyltransferase subunit II), which are deficient in de novo sphingosine biosynthesis, is increased when flies are raised in food supplemented with sphingosine. Arrestin mutant flies were raised under similar conditions and their photoreceptors were examined by electron microscopy. The rhabdomeres of R1 to R6 cells showed no suppression; instead, they showed enhanced degeneration of these photoreceptors. Thus, it is believed that sphingosine on its own is not a likely candidate for suppression of degeneration in the present study; instead, suppression correlated with decreased ceramide levels in rescued mutant flies (Acharya, 2003).
Ceramidase suppressed degeneration in arr23 mutants with chronically active rhodopsin and defects in clathrin-dependent endocytosis. It is possible that ceramidase suppressed degeneration by altering the balance of the endocytic pathway, thereby alleviating cytotoxicity arising from defective endocytosis. To test this, ceramidase was expressed in a dynamin mutant background in the eye. Dynamin is a guanosine triphosphatase essential for clathrin-mediated endocytosis. In Drosophila, a temperature-sensitive mutant of dynamin, shibire (shits1), has a general defect in endocytosis. These results were recapitulated in mammalian cells when a similar mutant dynamin was overexpressed. A temperature-sensitive dominant-negative mutant, UAS-shits1, under the control of a GMR-Gal4 driver, was used to preferentially express the mutant protein in the eye. These photoreceptors showed profound retinal degeneration characterized by loss of rhabdomere and accumulation of multivesicular bodies and vacuoles in R1 to R6, whereas R7 was largely unaffected. Ceramidase expression suppressed degeneration in UAS-shits1 photoreceptors. Rhabdomeres were largely intact, vacuolated cells were fewer, and trapezoidal arrangement of rhabdomeres was retained. As in other degenerating mutants, rhodopsin levels were low in shits1 mutants compared with those of the wild type but were restored upon ceramidase expression (Acharya, 2003).
Whether SPT, the rate-limiting enzyme of the de novo sphingolipid biosynthetic pathway, could affect the degeneration observed in these mutants was tested. In Drosophila, the Lace gene encodes the LCB2 subunit of SPT. The P-lacW-inserted lace allele l(2)k05305 is an insertion of a P-element 8 to 9 base pairs upstream of the transcription start site of lace and is homozygous lethal. arr23 and UAS-shits1 mutants were crossed into the lace heterozygous background and photoreceptors were examined by transmission electron microscopy. lace heterozygotes had intact photoreceptors. lace partially suppressed retinal degeneration in arr23 mutants and in UAS-shits1 mutants (Acharya, 2003).
Finally, whether ceramidase and lace suppressed degeneration in a phospholipase C mutant, where endocytosis has been implicated in the degenerative process, was examined. Norp A encodes an eye-specific phospholipase C that activates GPCR signaling by generating inositol trisphosphate and diacylglycerol. norp A mutant flies do not show light-induced receptor potential and are blind. Although norp A mutants degenerated slowly, these changes were obvious even in 3-day-old flies. Expression of ceramidase in a norp A mutant suppressed retinal degeneration. Lace heterozygotes also suppressed norp A degeneration. arr23 mutants undergo necrotic cell death, whereas norp A mutants accumulate rhodopsin-arrestin complexes and undergo apoptotic cell death. Thus, regardless of the mode of cell death ceramidase expression and lace mutant rescued degeneration. Because they also suppressed degeneration in a dynamin mutant, it is inferred that the sphingolipid pathway exerts its beneficial effect by altering the dynamics of the endocytic process. This is supported by observations that a sphingoid base is required for yeast endocytosis and that in mammalian cells ceramide analogs modulate fluid-phase and receptor-mediated endocytosis (Acharya, 2003).
The molecular details of suppression of retinal degeneration by ceramidase overexpression and lace mutant remain to be elucidated. A common denominator in both situations is the likely decrease in concentrations of ceramide, which could be responsible for activating a cascade that suppresses degeneration (Acharya, 2003).
A large volume of work suggests that receptor desensitization, endocytosis, and recycling play a crucial role in GPCR signaling in higher organisms. In light of the current finding, it will be interesting to study sphingolipid metabolism in GPCR-mediated processes. Several inherited forms of human retinal degenerations result from mutations in rhodopsin, arrestin, and phosphodiesterase, among others. Individuals with Oguchi disease have mutations in visual arrestin and a form of degenerative night blindness. Rescue of degeneration in Drosophila visual mutants provides a strong basis for exploring strategies that manipulate sphingolipid enzymes for therapeutic management of retinal degeneration in higher organisms (Acharya, 2003).
Neutral ceramidase, a key enzyme of sphingolipid metabolism (see Long-chain base synthesis resulting in ceramide formation from Shayman, 2000), hydrolyzes ceramide to sphingosine. These sphingolipids are critical structural components of cell membranes and act as second messengers in diverse signal transduction cascades. This study isolated and characterized functional null mutants of Drosophila ceramidase. Secreted ceramidase functions in a cell-nonautonomous manner to maintain photoreceptor homeostasis. In the absence of ceramidase, photoreceptors degenerate in a light-dependent manner, are defective in normal endocytic turnover of rhodopsin, and do not respond to light stimulus. Consistent with a cell-nonautonomous function, overexpression of ceramidase in tissues distant from photoreceptors suppresses photoreceptor degeneration in an arrestin mutant and facilitates membrane turnover in a rhodopsin null mutant. Furthermore, the results show that secreted ceramidase is internalized and localizes to endosomes. These findings establish a role for a secreted sphingolipid enzyme in the regulation of photoreceptor structure and function (Acharya, 2008).
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