Impaired calcium (Ca
2+) homeostasis is observed in neurons in diabetic neuropathy,
11 as well as in DR.
12–14 Dysregulation of intracellular Ca
2+ levels causes neuronal death and contributes to neurodegenerative diseases.
15 In the retina, impaired Ca
2+ homeostasis due to environmental stresses, such as bright light or heavy metal toxicity, leads to photoreceptor apoptosis and retinal degeneration,
16,17 emphasizing the importance of Ca
2+ homeostasis for neuronal survival. Calcium is highly compartmentalized in the retinal photoreceptor,
18,19 and intracellular Ca
2+ homeostasis is dynamically regulated by Ca
2+ channels, transporters, and intracellular Ca
2+ stores.
19 Calcium influx through L-type voltage-gated calcium channels (L-VGCCs), the major Ca
2+ channel present in the photoreceptor inner segments and synaptic terminals, is essential for neurotransmitter release, Ca
2+ homeostasis, and other cellular processes.
18,20,21 Mutations of the L-VGCCα1 subunit cause a defect in photoreceptor neurotransmission and congenital blindness.
22–25 In several inherited retinal degeneration diseases, abnormal intracellular Ca
2+ concentration is often observed in apoptotic photoreceptors.
26,27 The Ca
2+ influx via L-VGCCs activates phospholipase C (PLC) and triggers a release of Ca
2+ from the endoplasmic reticulum (ER) Ca
2+ stores, which increases intracellular Ca
2+ concentration,
18,28,29 subsequently activating multiple cellular responses, including Ca
2+ uptake/refilling by ER, metabolism, and gene expression.
18,28,29 The PLC-dependent increase of intracellular Ca
2+ concentration then induces feedback regulation and modulates L-VGCC activities in cones
30 and other cell types.
31–35 Plasma membrane Ca
2+ ATPase 1 (PMCA1) is another critical player in Ca
2+ homeostasis
36 by extruding excess Ca
2+ at the synaptic terminals of photoreceptors and other retinal neurons.
28,37,38 Importantly, the L-VGCCs regulate PMCA1 trafficking and translocation into the plasma membrane at the photoreceptor synaptic terminals.
39 Hence, Ca
2+ influx through L-VGCCs leads to changes in ER Ca
2+ stores and PMCA1, with further feedback modulation on L-VGCCs. The dynamics among L-VGCCs, intracellular Ca
2+ stores, and PMCA1 are responsible for maintaining Ca
2+ homeostasis and overall health of photoreceptors.