Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors

Abstract

Calcium plays important roles in the function and survival of rod and cone photoreceptor cells. Rapid regulation of calcium in the outer segments of photoreceptors is required for the modulation of phototransduction that drives the termination of the flash response as well as light adaptation in rods and cones. On a slower time scale, maintaining proper calcium homeostasis is critical for the health and survival of photoreceptors. Decades of work have established that the level of calcium in the outer segments of rods and cones is regulated by a dynamic equilibrium between influx via the transduction cGMP-gated channels and extrusion via rod- and cone-specific Na+/Ca2+, K+ exchangers (NCKXs). It had been widely accepted that the only mechanism for extrusion of calcium from rod outer segments is via the rod-specific NCKX1, while extrusion from cone outer segments is driven exclusively by the cone-specific NCKX2. However, recent evidence from mice lacking NCKX1 and NCKX2 have challenged that notion and have revealed a more complex picture, including a NCKX-independent mechanism in rods and two separate NCKX-dependent mechanisms in cones. This review will focus on recent findings on the molecular mechanisms of extrusion of calcium from the outer segments of rod and cone photoreceptors, and the functional and structural changes in photoreceptors when normal extrusion is disrupted.

Systematic spatiotemporal mapping reveals divergent cell death pathways in three mouse models of hereditary retinal degeneration

“…This is probably due to the low number of cones in the mouse retina and the stochastic nature of the cell death seen in all mouse models of retinal dystrophies (Clarke et al, 2000). It is also possible that due to differences in the phototransduction machinery cones are more resilient to Ca 2+ based cell death mechanisms when compared to rods (Vinberg, Chen, & Kefalov, 2018).…”

Increasing Ca2+ in photoreceptor mitochondria alters metabolites, accelerates photoresponse recovery, and reveals adaptations to mitochondrial stress

“…Photoreceptors rely on Ca 2+ as a second messenger for recovery from transient light signals, adaptation to constant illumination, and neurotransmission [1,2]. Both chronic elevations and chronic decreases in cytosolic Ca 2+ have been implicated in photoreceptor cell death and retinal disease [3,4]. Ca 2+ -associated cell death is often mediated by mitochondria, as mitochondrial Ca 2+ overload triggers opening of the mitochondrial permeability transition pore (mPTP) and subsequent cell death [5].…”

Mitochondrial Ca2+influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

“…Cytosolic Ca 2+ in the photoreceptor outer segments regulates the gain of phototransduction, light response recovery kinetics and light adaptation mainly via GCAPs- and recoverin-mediated pathways both in rods and cones (Makino et al, 2004; Mendez et al, 2001; Sakurai et al, 2011, 2015). Compared to rod photoreceptors, cone phototransduction gain is smaller and cones recover faster to the dark-adapted state after transient light stimulus (for recent review, see Vinberg et al, 2018). These differences are believed to stem, at least partly, from the faster clearance of cytosolic Ca 2+ in cone as compared to rod outer segments (Sampath et al, 1998, 1999).…”

“…Extrusion of Ca 2+ from the outer segment of photoreceptors is thought to be accomplished primarily by plasma membrane Na+/Ca 2+ , K+ exchangers NCKX1 in rods, and NCKX2 and NCKX4 in cones (for recent review, see Vinberg et al, 2018). However, Nckx1 −/− rods appear to clear cytosolic Ca 2+ through a slower, yet unidentified mechanism (Vinberg et al, 2015a).…”

“…In darkness they continuously release synaptic vesicles, which requires precise regulation of synaptic Ca 2+ by L-type voltage-gated channels (Barnes and Kelly, 2002). Both chronic elevations and chronic decreases in cytosolic Ca 2+ have been implicated in photoreceptor cell death and retinal disease (for review, see Fain, 2006; Vinberg et al, 2018). Mutations in photoreceptor phosphodiesterase, guanylyl cyclase, and guanylyl cyclase activating protein result in sustained high Ca 2+ in the cell and cause retinal degeneration (Bowes et al, 1990; Dizhoor et al, 1998; Fox et al, 1999; Payne et al, 1998; Sokal et al, 1998; Tucker et al, 1999; Wilkie et al, 2000).…”