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5.2 Ca2+ Homeostasis in Photoreceptors
Vertebrates contain two types of photoreceptors: rods responsible for vision in dim
light, and cones, which respond to bright light and mediate color vision.
Photoreceptors are highly polarized and consist of three main subcellular domains:
the outer segment (the site of phototransduction), the cell body (the site of major
organelles and the nucleus), and the synapse (the site of neurotransmitter release).
This segregation of function requires that the different cellular compartments care-
fully regulate signaling molecules involved in multiple cellular processes.
Ca2+ plays vital roles in cellular processes in all compartments [ 1 ]. For example,Ca2+ regulates photoresponse recovery and adaptation in the outer segment [ 2 ],
metabolism [ 3 – 7 ] and protein trafficking [ 8 , 9 ] in the cell body, and synaptic trans-
mission at the synapse [ 10 – 13 ]. Furthermore, perturbations in cellular Ca2+ are
associated with photoreceptor cell death. Mutations in photoreceptor phosphodies-
terase and guanylate cyclase activating protein both result in sustained high Ca2+ in
the cell and cause retinal degeneration [ 14 – 16 ]. Sustained light exposure, rhodopsin
kinase knockouts, and arrestin knockouts cause sustained low intracellular Ca2+ and
also cause retinal degeneration [ 17 – 19 ].
Each compartment of the photoreceptor uses different mechanisms for regulat-ing Ca2+ levels [ 1 ]. Kinetics of Ca2+ clearance from the outer segment and the cell
body/synapse are markedly different, with the outer segment extruding Ca2+ at a
much faster rate than the rest of the cell [ 20 ]. Ca2+ in the outer segment must be
cleared quickly to mediate rapid visual responses to changes in illumination. Ca2+ in
the cell body coordinates cellular processes such as gene expression and metabolic
flux, which occur on a slower time scale. Ca2+ flow through the cell is mediated by
the endoplasmic reticulum (ER), which extends from the synapse to the cell body
[ 21 , 22 ]. Mitochondria tend to cluster in photoreceptor cell bodies where they both
regulate intracellular Ca2+ levels and functionally integrate cellular Ca2+ dynamics
[ 23 , 24 ]. In zebrafish cones, large clusters of 80–100 individual mitochondria aggre-
gate at the apical end of the inner segment [ 24 , 25 ]. These mitochondria vary drasti-
cally in morphology and size most likely reflecting different cellular roles. Most of
the details regarding the role of the ER and mitochondria in photoreceptor Ca2+
homeostasis are unknown.
The recent identification of the mitochondrial calcium uniporter (MCU) providesthe opportunity to genetically dissect the consequence of altered Ca2+ uptake into
mitochondria on photoreceptor viability and function (Fig. 5.1). The membrane-
spanning MCU, together with regulatory proteins, is thought to control influx of
Ca2+ into mitochondria [ 28 ]. Ca2+ has vital roles in regulating mitochondrial func-
tion. Uptake of Ca2+ into mitochondria regulates bioenergetics by lowering Km’s of
dehydrogenases that produce NADH (pyruvate dehydrogenase, isocitrate dehydro-
genase, and α-KG dehydrogenase) [ 29 – 31 ]. Ca2+ also increases NADH consump-
tion by increasing F1-F0 ATP synthase activity [ 5 , 32 ]. However, excess
mitochondrial Ca2+ can be very detrimental to the cell and lead to activation of cell
death pathways [ 33 ]. Ca2+ can increase free radical production through elevated
S.E. Brockerhoff