Light Activation, Adaptation, and Cell Survival Functions of the Na+/Ca2+ Exchanger CalX

Abstract

In sensory neurons, Ca(2+) entry is crucial for both activation and subsequent attenuation of signaling. Influx of Ca(2+) is counterbalanced by Ca(2+) extrusion, and Na(+)/Ca(2+) exchange is the primary mode for rapid Ca(2+) removal during and after sensory stimulation. However, the consequences on sensory signaling resulting from mutations in Na(+)/Ca(2+) exchangers have not been described. Here, we report that mutations in the Drosophila Na(+)/Ca(2+) exchanger calx have a profound effect on activity-dependent survival of photoreceptor cells. Loss of CalX activity resulted in a transient response to light, a dramatic decrease in signal amplification, and unusually rapid adaptation. Conversely, overexpression of CalX had reciprocal effects and greatly suppressed the retinal degeneration caused by constitutive activity of the TRP channel. These results illustrate the critical role of Ca(2+) for proper signaling and provide genetic evidence that Ca(2+) overload is responsible for a form of retinal degeneration resulting from defects in the TRP channel.

Phototransduction and retinal degeneration in Drosophila

“…Analyses of the calx mutant, as well as flies overexpressing calx, show that Ca 2+ extrusion through the Na + / Ca 2+ exchanger is required for many events during phototransduction [157] and support other studies indicating that Ca 2+ both facilitates and inhibits different aspects of the photoresponse [25]. Loss of calx results in an inability to sustain a photoresponse of normal amplitude (Fig.…”

“…In Drosophila photoreceptor cells, a Na + /Ca 2+ exchanger, CalX (Fig. 1) [154][155][156], colocalizes with TRP in the rhabdomeres and is the critical protein that mediates extrusion of Ca 2+ [157]. As is typical of other Na + /Ca 2+ exchangers, CalX extrudes one Ca 2+ ion in exchange for entry of three Na + ions [154][155][156].…”

“…Loss of calx results in an inability to sustain a photoresponse of normal amplitude (Fig. 3d), hyperadaptation, possibly due to Ca 2+ -mediated inactivation of the TRP channels, and decreased amplification [157].…”

Proper splicing contributes to visual function in the aging Drosophila eye

“…However, we also detected alternative transcription start site usage and differential splicing events in both the 5′ and 3′ untranslated regions, which could represent alternative promoter usage and/or polyadenylation. The genes that were differentially spliced with age in the eye were enriched for somewhat broad GO categories including negative regulation of neuron differentiation and cell–cell signaling and include genes that have previously been shown to play a role in visual function in flies including discs large 1 (dlg1) , branchless (bnl), and Na/Ca‐exchange protein ( Calx ; Mendoza‐Topaz et al, 2008; Mukherjee, Choi, & Banerjee, 2012; Wang et al, 2005). The Drosophila compound eye contains a number of cell types in addition to photoreceptors including additional structural and pigment cells (Ready, Hanson, & Benzer, 1976).…”

“…For example, Calx encodes a calcium/sodium exchange channel that suppresses retinal degeneration caused by toxic levels of calcium in photoreceptors, a consequence of light stress in flies (Chen et al, 2017; Wang et al, 2005). We observed both differential splicing and circRNA increases at Calx (Supporting Information Figure S3).…”