RESUMEN
The sense of taste provides animals with valuable information about the quality and nutritional value of food. Previously, we identified a large family of mammalian taste receptors involved in bitter taste perception (the T2Rs). We now report the characterization of mammalian sweet taste receptors. First, transgenic rescue experiments prove that the Sac locus encodes T1R3, a member of the T1R family of candidate taste receptors. Second, using a heterologous expression system, we demonstrate that T1R2 and T1R3 combine to function as a sweet receptor, recognizing sweet-tasting molecules as diverse as sucrose, saccharin, dulcin, and acesulfame-K. Finally, we present a detailed analysis of the patterns of expression of T1Rs and T2Rs, thus providing a view of the representation of sweet and bitter taste at the periphery.
Asunto(s)
Receptores de Superficie Celular/metabolismo , Receptores Acoplados a Proteínas G , Edulcorantes , Papilas Gustativas/química , Papilas Gustativas/metabolismo , Gusto/fisiología , Animales , Señalización del Calcio , Línea Celular , Cromosomas Humanos Par 4/genética , Cricetinae , Evolución Molecular , Perfilación de la Expresión Génica , Prueba de Complementación Genética , Proteínas de Unión al GTP Heterotriméricas/genética , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Humanos , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Familia de Multigenes , Compuestos de Fenilurea/metabolismo , Mapeo Físico de Cromosoma , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Sacarina/metabolismo , Especificidad por Sustrato , Sacarosa/metabolismo , Papilas Gustativas/citología , Tiazinas/metabolismoRESUMEN
Light-induced photoreceptor apoptosis occurs in many forms of inherited retinal degeneration resulting in blindness in both vertebrates and invertebrates. Though mutations in several photoreceptor signaling proteins have been implicated in triggering this process, the molecular events relating light activation of rhodopsin to photoreceptor death are yet unclear. Here, we uncover a pathway by which activation of rhodopsin in Drosophila mediates apoptosis through a G protein-independent mechanism. This process involves the formation of membrane complexes of phosphorylated, activated rhodopsin and its inhibitory protein arrestin, and subsequent clathrin-dependent endocytosis of these complexes into a cytoplasmic compartment. Together, these data define the proapoptotic molecules in Drosophila photoreceptors and indicate a novel signaling pathway for light-activated rhodopsin molecules in control of photoreceptor viability.
Asunto(s)
Apoptosis , Proteínas de Unión al Calcio , Proteínas de Drosophila , Drosophila/metabolismo , Luz/efectos adversos , Células Fotorreceptoras de Invertebrados/metabolismo , Degeneración Retiniana/metabolismo , Rodopsina/análogos & derivados , Animales , Arrestinas/metabolismo , Unión Competitiva/genética , Clatrina/metabolismo , Endocitosis , Regulación de la Expresión Génica , Mutación , Fosfoproteínas Fosfatasas/genética , Fosfoproteínas/metabolismo , Fosforilación , Células Fotorreceptoras de Invertebrados/patología , Rodopsina/metabolismoRESUMEN
We have investigated the role of the ryanodine receptor in Drosophila development by using pharmacological and genetic approaches. We identified a P element insertion in the Drosophila ryanodine receptor gene, Ryanodine receptor 44F (Ryr), and used it to generate the hypomorphic allele Ryr(16). An examination of hypodermal, visceral, and circulatory muscle showed that, in each case, muscle contraction was impaired in Ryr(16) larvae. Treatment with the drug ryanodine, a highly specific modulator of ryanodine receptor channel activity, also inhibited muscle function, and, at high levels, completely blocked hypodermal muscle contraction. These results suggest that the ryanodine receptor is required for proper muscle function and may be essential for excitation-contraction coupling in larval body wall muscles. Nonmuscle roles of Ryr were also investigated. Ryanodine-sensitive Ca(2+) stores had previously been implicated in phototransduction; to address this, we generated Ryr(16) mutant clones in the adult eye and performed whole-cell, patch-clamp recordings on dissociated ommatidia. Our results do not support a role for Ryr in normal light responses.
Asunto(s)
Señalización del Calcio/fisiología , Drosophila melanogaster/crecimiento & desarrollo , Canal Liberador de Calcio Receptor de Rianodina/fisiología , Alelos , Animales , Elementos Transponibles de ADN , Drosophila melanogaster/metabolismo , Motilidad Gastrointestinal , Hibridación Fluorescente in Situ , Larva , Contracción Muscular , Desarrollo de Músculos , Contracción Miocárdica , Técnicas de Placa-Clamp , Reacción en Cadena de la Polimerasa , Rianodina/farmacología , Canal Liberador de Calcio Receptor de Rianodina/deficiencia , Canal Liberador de Calcio Receptor de Rianodina/efectos de los fármacos , Canal Liberador de Calcio Receptor de Rianodina/genéticaRESUMEN
In mammals, taste perception is a major mode of sensory input. We have identified a novel family of 40-80 human and rodent G protein-coupled receptors expressed in subsets of taste receptor cells of the tongue and palate epithelia. These candidate taste receptors (T2Rs) are organized in the genome in clusters and are genetically linked to loci that influence bitter perception in mice and humans. Notably, a single taste receptor cell expresses a large repertoire of T2Rs, suggesting that each cell may be capable of recognizing multiple tastants. T2Rs are exclusively expressed in taste receptor cells that contain the G protein alpha subunit gustducin, implying that they function as gustducin-linked receptors. In the accompanying paper, we demonstrate that T2Rs couple to gustducin in vitro, and respond to bitter tastants in a functional expression assay.
Asunto(s)
Células Quimiorreceptoras/fisiología , Proteínas de la Membrana/genética , Receptores de Superficie Celular/genética , Receptores Acoplados a Proteínas G , Papilas Gustativas/fisiología , Gusto/fisiología , Animales , Células Quimiorreceptoras/química , Clonación Molecular , Evolución Molecular , Proteínas de Unión al GTP/metabolismo , Expresión Génica/fisiología , Humanos , Mamíferos , Proteínas de la Membrana/análisis , Proteínas de la Membrana/metabolismo , Ratones , Datos de Secuencia Molecular , Familia de Multigenes/fisiología , ARN Mensajero/análisis , Ratas , Receptores de Superficie Celular/análisis , Receptores de Superficie Celular/metabolismo , Homología de Secuencia de Aminoácido , Transducina/análisis , Transducina/genética , Transducina/metabolismoRESUMEN
Bitter taste perception provides animals with critical protection against ingestion of poisonous compounds. In the accompanying paper, we report the characterization of a large family of putative mammalian taste receptors (T2Rs). Here we use a heterologous expression system to show that specific T2Rs function as bitter taste receptors. A mouse T2R (mT2R-5) responds to the bitter tastant cycloheximide, and a human and a mouse receptor (hT2R-4 and mT2R-8) responded to denatonium and 6-n-propyl-2-thiouracil. Mice strains deficient in their ability to detect cycloheximide have amino acid substitutions in the mT2R-5 gene; these changes render the receptor significantly less responsive to cycloheximide. We also expressed mT2R-5 in insect cells and demonstrate specific tastant-dependent activation of gustducin, a G protein implicated in bitter signaling. Since a single taste receptor cell expresses a large repertoire of T2Rs, these findings provide a plausible explanation for the uniform bitter taste that is evoked by many structurally unrelated toxic compounds.
Asunto(s)
Células Quimiorreceptoras/química , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores Acoplados a Proteínas G , Papilas Gustativas/química , Gusto/fisiología , Vías Aferentes/química , Vías Aferentes/fisiología , Secuencia de Aminoácidos , Animales , Calcio/análisis , Línea Celular , Células Quimiorreceptoras/fisiología , Cicloheximida , Expresión Génica/fisiología , Humanos , Riñón/citología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Datos de Secuencia Molecular , Inhibidores de la Síntesis de la Proteína , Compuestos de Amonio Cuaternario , Receptores de Superficie Celular/análisis , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal/fisiología , Papilas Gustativas/fisiología , Transducina/metabolismo , TransfecciónRESUMEN
Mechanosensory transduction underlies a wide range of senses, including proprioception, touch, balance, and hearing. The pivotal element of these senses is a mechanically gated ion channel that transduces sound, pressure, or movement into changes in excitability of specialized sensory cells. Despite the prevalence of mechanosensory systems, little is known about the molecular nature of the transduction channels. To identify such a channel, we analyzed Drosophila melanogaster mechanoreceptive mutants for defects in mechanosensory physiology. Loss-of-function mutations in the no mechanoreceptor potential C (nompC) gene virtually abolished mechanosensory signaling. nompC encodes a new ion channel that is essential for mechanosensory transduction. As expected for a transduction channel, D. melanogaster NOMPC and a Caenorhabditis elegans homolog were selectively expressed in mechanosensory organs.
Asunto(s)
Proteínas de Drosophila , Drosophila melanogaster/fisiología , Canales Iónicos/genética , Canales Iónicos/fisiología , Mecanorreceptores/fisiología , Neuronas Aferentes/fisiología , Potenciales de Acción , Adaptación Fisiológica , Secuencia de Aminoácidos , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiología , Mapeo Cromosómico , Clonación Molecular , Dendritas/fisiología , Drosophila melanogaster/genética , Perfilación de la Expresión Génica , Genes de Insecto , Células Ciliadas Auditivas/fisiología , Proteínas de Insectos/química , Proteínas de Insectos/genética , Proteínas de Insectos/fisiología , Canales Iónicos/química , Datos de Secuencia Molecular , Mutación , Técnicas de Placa-Clamp , Estimulación Física , Propiocepción , Sensación/fisiología , Órganos de los Sentidos/fisiología , Transducción de Señal , Tacto , Canales de Potencial de Receptor TransitorioRESUMEN
Taste represents a major form of sensory input in the animal kingdom. In mammals, taste perception begins with the recognition of tastant molecules by unknown membrane receptors localized on the apical surface of receptor cells of the tongue and palate epithelium. We report the cloning and characterization of two novel seven-transmembrane domain proteins expressed in topographically distinct subpopulations of taste receptor cells and taste buds. These proteins are specifically localized to the taste pore and are members of a new group of G protein-coupled receptors distantly related to putative mammalian pheromone receptors. We propose that these genes encode taste receptors.
Asunto(s)
Proteínas de Unión al GTP/genética , Receptores de Superficie Celular/genética , Receptores Acoplados a Proteínas G , Células Receptoras Sensoriales/química , Células Receptoras Sensoriales/fisiología , Papilas Gustativas/química , Papilas Gustativas/fisiología , Animales , Anticuerpos , Expresión Génica/fisiología , Humanos , Hibridación in Situ , Mamíferos , Ratones , Datos de Secuencia Molecular , Neuronas Aferentes/química , Neuronas Aferentes/fisiología , ARN Mensajero/análisis , Conejos , Ratas , Receptores de Superficie Celular/análisis , Receptores de Superficie Celular/inmunología , Homología de Secuencia de Aminoácido , Transducción de Señal/fisiología , Transducina/análisisAsunto(s)
Arrestina/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transducción de Señal , Animales , Arrestina/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Membrana Celular/metabolismo , Activación Enzimática , Proteínas de Unión al GTP/metabolismo , Humanos , Modelos Biológicos , Mutación , Fosforilación , Receptor Cross-Talk , Dominios Homologos srcRESUMEN
Phototransduction in Drosophila has emerged as an attractive model system for studying the organization of signaling cascades in vivo. In photoreceptor neurons, the multivalent PDZ protein INAD serves as a scaffold to assemble different components of the phototransduction pathway, including the effector PLC, the light-activated ion channel TRP, and a protein kinase C involved in deactivation of the light response. INAD is required for organizing and maintaining signaling complexes in the rhabdomeres of photoreceptors. This macromolecular organization endows photoreceptors with many of their signaling properties, including high sensitivity, fast activation and deactivation kinetics, and exquisite feedback regulation by small localized changes in [Ca2+]i. Assembly of transduction components into signaling complexes is also an important cellular strategy for ensuring specificity of signaling while minimizing unwanted cross-talk. In this report, we review INAD's role as a signal transduction scaffold and its role in the assembly and localization of photoreceptor complexes.
Asunto(s)
Drosophila/fisiología , Proteínas del Ojo/fisiología , Proteínas de la Membrana , Células Fotorreceptoras de Invertebrados/fisiología , Transducción de Señal/fisiología , Animales , Proteínas de Uniones EstrechasRESUMEN
The subcellular compartmentalization of signalling molecules helps to ensure the selective activation of different signal-transduction cascades within a single cell. Although there are many examples of compartmentalized signalling molecules, there are few examples of entire signalling cascades being organized as distinct signalling complexes. In Drosophila photoreceptors, the InaD protein, which consists of five PDZ domains, functions as a multivalent adaptor that brings together several components of the phototransduction cascade into a macromolecular complex. Here we study single-photon responses in several photoreceptor mutant backgrounds, and show that the InaD macromolecular complex is the unit of signalling that underlies elementary responses. We show that the localized activity of this signalling unit promotes reliable single-photon responses as well as rapid activation and feedback regulation. Finally, we use genetic and electrophysiological tools to illustrate how the assembly of signalling molecules into a transduction complex limits signal amplification in vivo.
Asunto(s)
Proteínas de Drosophila , Proteínas del Ojo/metabolismo , Células Fotorreceptoras de Invertebrados/metabolismo , Transducción de Señal , Visión Ocular , Animales , Calmodulina/genética , Calmodulina/metabolismo , Drosophila , Proteínas del Ojo/genética , Proteínas de Unión al GTP/metabolismo , Luz , Mutación , Técnicas de Placa-Clamp , Rodopsina/metabolismoRESUMEN
A critical issue in the field of signal transduction is how signaling molecules are organized into different pathways within the same cell. The importance of assembling signaling molecules into architecturally defined complexes is emerging as an essential cellular strategy to ensure specificity and selectivity of signaling. Scaffold proteins function as the pillars of these transduction complexes, bringing together a diversity of signaling components into defined ultramicrodomains of signaling.
Asunto(s)
Transducción de Señal , Animales , Fracciones SubcelularesRESUMEN
Phosphoinositides function as important second messengers in a wide range of cellular processes. Inositol polyphosphate 1-phosphatase (IPP) is an enzyme essential for the hydrolysis of the 1-phosphate from either Ins(1,4)P2 or Ins(1,3,4)P3. This enzyme is Li+ sensitive, and is one of the proposed targets of Li+ therapy in manic-depressive illness. Drosophila ipp mutants accumulate IP2 in their system and are incapable of metabolizing exogenous Ins(1,4)P2. Notably, ipp mutants demonstrate compensatory upregulation of an alternative branch in the inositol-phosphate metabolism tree, thus providing a means of ensuring continued availability of inositol. We demonstrate that ipp mutants have a defect in synaptic transmission resulting from a dramatic increase in the probability of vesicle release at larval neuromuscular junctions. We also show that Li+ phenocopies this effect in wild-type synapses. Together, these results support a role for phosphoinositides in synaptic vesicle function in vivo and mechanistically question the "lithium hypothesis."
Asunto(s)
Drosophila/genética , Fosfatos de Inositol/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Transmisión Sináptica/fisiología , Animales , Mapeo Cromosómico , Clonación Molecular , Drosophila/enzimología , Electrofisiología , Femenino , Regulación Enzimológica de la Expresión Génica/fisiología , Litio/farmacología , Masculino , Datos de Secuencia Molecular , Mutación/fisiología , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neurotransmisores/metabolismo , Homología de Secuencia de Aminoácido , Especificidad por Sustrato , Vesículas Sinápticas/metabolismoRESUMEN
Calmodulin (CAM) participates in a variety of intracellular transduction processes by modulating signaling molecules in response to calcium changes. We report the characterization of Drosophila Cam mutants and the role of CAM in photoreceptor cell function. Contrary to current models of excitation and TRP channel function, we demonstrate that the transient phenotype of trp mutants can be explained by CAM regulation of the TRPL channel rather than by the loss of a store-operated conductance leading to depletion of the internal stores. We also analyzed light responses in a variety of mutant and transgenic backgrounds and demonstrate the importance of calmodulin in mediating calcium-dependent negative regulation of phototransduction. Our results show that CAM coordinates termination of the light response by modulating receptor and ion channel activity.
Asunto(s)
Proteínas de Unión a Calmodulina/metabolismo , Calmodulina/metabolismo , Proteínas de Drosophila , Drosophila/metabolismo , Canales Iónicos/metabolismo , Proteínas de la Membrana/metabolismo , Células Fotorreceptoras de Invertebrados/metabolismo , Animales , Calcio/metabolismo , Calmodulina/genética , Drosophila/genética , Luz , Mutación , Rodopsina/metabolismo , Canales de Potencial de Receptor Transitorio , Visión OcularRESUMEN
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors are phosphorylated by kinases that mediate agonist-dependent receptor deactivation. Although many receptor kinases have been isolated, the corresponding phosphatases, necessary for restoring the ground state of the receptor, have not been identified. Drosophila RDGC (retinal degeneration C) is a phosphatase required for rhodopsin dephosphorylation in vivo. Loss of RDGC caused severe defects in the termination of the light response as well as extensive light-dependent retinal degeneration. These phenotypes resulted from the hyperphosphorylation of rhodopsin because expression of a truncated rhodopsin lacking the phosphorylation sites restored normal photoreceptor function. These results suggest the existence of a family of receptor phosphatases involved in the regulation of G protein-coupled signaling cascades.
Asunto(s)
Proteínas de Unión al Calcio , Proteínas de Drosophila , Proteínas de Unión al GTP/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Células Fotorreceptoras de Invertebrados/metabolismo , Rodopsina/metabolismo , Animales , Animales Modificados Genéticamente , Arrestina/metabolismo , Oscuridad , Drosophila , Electrorretinografía , Luz , Mutación , Fosfoproteínas Fosfatasas/genética , Fosforilación , Retina/metabolismo , Degeneración Retiniana , Transducción de SeñalRESUMEN
How are signalling molecules organized into different pathways within the same cell? In Drosophila, the inaD gene encodes a protein consisting of five PDZ domains which serves as a scaffold to assemble different components of the phototransduction cascade, including the principal light-activated ion channels, the effector phospholipase C-beta and protein kinase C. Null inaD mutants have a dramatically reorganized subcellular distribution of signalling molecules, and a total loss of transduction complexes. Also, mutants defective in a single PDZ domain produce signalling complexes that lack the target protein and display corresponding defects in their physiology. A picture emerges of a highly organized unit of signalling, a 'transduclisome', with PDZ domains functioning as key elements in the organization of transduction complexes in vivo.
Asunto(s)
Proteínas de Drosophila , Proteínas del Ojo/metabolismo , Proteínas de Unión al GTP/metabolismo , Transducción de Señal , Secuencia de Aminoácidos , Animales , Sitios de Unión , Canales de Calcio/metabolismo , Drosophila , Electrofisiología , Proteínas del Ojo/química , Proteínas del Ojo/genética , Femenino , Proteínas de Insectos/metabolismo , Masculino , Datos de Secuencia Molecular , Mutación , Células Fotorreceptoras de Invertebrados/metabolismo , Células Fotorreceptoras de Invertebrados/ultraestructura , Proteína Quinasa C/metabolismo , Homología de Secuencia de Aminoácido , Canales de Potencial de Receptor Transitorio , Fosfolipasas de Tipo C/metabolismo , Visión OcularRESUMEN
Phospholipase C (PLC) is the focal point for two major signal transduction pathways: one initiated by G protein-coupled receptors and the other by tyrosine kinase receptors. Active PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) into the two second messengers inositol 1,4,5-trisphosphate (InsP3) and diacyl glycerol (DAG). DAG activates protein kinase C, and InsP3 mobilizes calcium from intracellular stores via the InsP3 receptor. Changes in [Ca2+]i regulate the function of a wide range of target proteins, including ion channels, kinases, phosphatases, proteases, and transcription factors (Berridge, 1993). In the mouse, there are three InsP3R genes, and type 1 InsP3R mutants display ataxia and epileptic seizures (Matsumoto et al., 1996). In Drosophila, only one InsP3 receptor (InsP3R) gene is known, and it is expressed ubiquitously throughout development (Hasan and Rosbash, 1992; Yoshikawa et al., 1992; Raghu and Hasan, 1995). Here, we characterize Drosophila InsP3R mutants and demonstrate that the InsP3R is essential for embryonic and larval development. Interestingly, maternal InsP3R mRNA is sufficient for progression through the embryonic stages, but larval organs show asynchronous and defective cell divisions, and imaginal discs arrest early and fail to differentiate. We also generated adult mosaic animals and demonstrate that phototransduction, a model PLC pathway thought to require InsP3R, does not require InsP3R for signaling.
Asunto(s)
Canales de Calcio/fisiología , Drosophila melanogaster/fisiología , Receptores Citoplasmáticos y Nucleares/fisiología , Visión Ocular/fisiología , Animales , Diferenciación Celular , División Celular , Drosophila melanogaster/crecimiento & desarrollo , Genes de Insecto , Receptores de Inositol 1,4,5-Trifosfato , Larva/citología , Mutagénesis , Retina/citología , Eliminación de Secuencia , Fosfolipasas de Tipo C/fisiologíaRESUMEN
SUMMARY: Drosophila phototransduction is a G protein-coupled, calcium-regulated signaling cascade that serves as a model system for the dissection of phospholipase C (PLC) signaling in vivo. The Drosophila light-activated conductance is constituted in part by the transient receptor potential (trp) ion channel, yet trp mutants still display a robust response demonstrating the presence of additional channels. The transient receptor potential-like (trpl) gene encodes a protein displaying 40% amino acid identity with TRP. Mammalian homologs of TRP and TRPL recently have been isolated and postulated to encode components of the elusive I(crac) conductance. We now show that TRP and TRPL localize to the membrane of the transducing organelle, together with rhodopsin and PLC, consistent with a role in PLC signaling during phototransduction. To determine the function of TRPL in vivo, we isolated trpl mutants and characterized them physiologically and genetically. We demonstrate that the light-activated conductance is composed of TRP and TRPL ion channels and that each can be activated on its own. We also use genetic and electrophysiological tools to study the contribution of each channel type to the light response and show that TRP and TRPL can serve partially overlapping functions.
Asunto(s)
Canales de Calcio/metabolismo , Proteínas de Unión a Calmodulina/metabolismo , Proteínas de Drosophila , Drosophila/metabolismo , Hormonas de Insectos/metabolismo , Proteínas de Insectos , Proteínas de la Membrana/metabolismo , Secuencia de Aminoácidos , Animales , Canales de Calcio/genética , Canales de Calcio/efectos de la radiación , Proteínas de Unión a Calmodulina/genética , Proteínas de Unión a Calmodulina/efectos de la radiación , Drosophila/genética , Drosophila/efectos de la radiación , Femenino , Hormonas de Insectos/genética , Hormonas de Insectos/efectos de la radiación , Luz , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/efectos de la radiación , Datos de Secuencia Molecular , Mutación , Fotobiología , Células Fotorreceptoras de Invertebrados/metabolismo , Células Fotorreceptoras de Invertebrados/efectos de la radiación , Transducción de Señal , Canales de Potencial de Receptor TransitorioRESUMEN
Phototransduction systems in vertebrates and invertebrates share a great deal of similarity in overall strategy but differ significantly in the underlying molecular machinery. Both are rhodopsin-based G protein-coupled signaling cascades displaying exquisite sensitivity and broad dynamic range. However, light activation of vertebrate photoreceptors leads to activation of a cGMP-phosphodiesterase effector and the generation of a hyperpolarizing response. In contrast, activation of invertebrate photoreceptors, like Drosophila, leads to stimulation of phospholipase C and the generation of a depolarizing receptor potential. The comparative study of these two systems of phototransduction offers the opportunity to understand how similar biological problems may be solved by different molecular mechanisms of signal transduction. The study of this process in Drosophila, a system ideally suited to genetic and molecular manipulation, allows us to dissect the function and regulation of such a complex signaling cascade in its normal cellular environment. In this manuscript I review some of our recent findings and the strategies used to dissect this process.
Asunto(s)
Drosophila/fisiología , Células Fotorreceptoras de Invertebrados/fisiología , Transducción de Señal , Visión Ocular/fisiología , Animales , Calcio/metabolismo , Canales Iónicos/metabolismo , Canales Iónicos/efectos de la radiación , Luz , Fosfatidilinositoles/metabolismoRESUMEN
Retinitis pigmentosa (RP) is a group of hereditary human diseases that cause retinal degeneration and lead to eventual blindness. More than 25% of all RP cases in humans appear to be caused by dominant mutations in the gene encoding the visual pigment rhodopsin. The mechanism by which the mutant rhodopsin proteins cause dominant retinal degeneration is still unclear. Interestingly, the great majority of these mutants appear to produce misfolded rhodopsin. We now report the isolation and characterization of 13 rhodopsin mutations that act dominantly to cause retinal degeneration in Drosophila; four of these correspond to identical substitutions in human autosomal dominant RP patients. We demonstrate that retinal degeneration results from interference in the maturation of wild-type rhodopsin by the mutant proteins.