Calcium dynamics and regulation in horizontal cells of the vertebrate retina: lessons from teleosts

Abstract

Horizontal cells (HCs) are inhibitory interneurons of the vertebrate retina. Unlike typical neurons, HCs are chronically depolarized in the dark, leading to a constant influx of Ca²⁺ Therefore, mechanisms of Ca²⁺ homeostasis in HCs must differ from neurons elsewhere in the central nervous system, which undergo excitotoxicity when they are chronically depolarized or stressed with Ca²⁺ HCs are especially well characterized in teleost fish and have been used to unlock mysteries of the vertebrate retina for over one century. More recently, mammalian models of the retina have been increasingly informative for HC physiology. We draw from both teleost and mammalian models in this review, using a comparative approach to examine what is known about Ca²⁺ pathways in vertebrate HCs. We begin with a survey of Ca²⁺-permeable ion channels, exchangers, and pumps and summarize Ca²⁺ influx and efflux pathways, buffering, and intracellular stores. This includes evidence for Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-d-aspartate receptors and for voltage-gated Ca²⁺ channels. Special attention is given to interactions between ion channels, to differences among species, and in which subtypes of HCs these channels have been found. We then discuss a number of unresolved issues pertaining to Ca²⁺ dynamics in HCs, including a potential role for Ca²⁺ in feedback to photoreceptors, the role for Ca²⁺-induced Ca²⁺ release, and the properties and functions of Ca²⁺-based action potentials. This review aims to highlight the unique Ca²⁺ dynamics in HCs, as these are inextricably tied to retinal function.

Keywords: calcium; horizontal cell; ion channels; retina; teleost.

Fig. 1.

Ca²⁺ pathways and their regulation in teleost horizontal cells. 1: In darkness, glutamate (red circles) is released from photoreceptors and binds onto HC glutamate receptors, allowing Ca²⁺ influx through Ca²⁺-permeable AMPARs and NMDARs and leading to depolarization of the plasma membrane. 2: Depolarization also opens VGCCs, including L-type and (at least in bass) T-type VGCCs. 3: Glutamate receptors acidify the cytosol, downregulating L-type VGCCs. In contrast, group I and/or III metabotropic glutamate receptors may upregulate VGCCs (see text). 4: Additionally, glutamate triggers CICR from RyRs, further downregulating L-type VGCCs. 5 and 6: The SERCA pump then refills Ca²⁺ stores, along with SOCs and/or NCXs functioning in reverse. 7: IP3Rs have been found in catfish but do not contribute to CICR. 8: Gap junctions and hemichannels might allow Ca²⁺ flow between coupled cells or with the extracellular environment in some conditions. 9: Ca²⁺ influx from AMPARs, NMDARs, and VGCCs is extruded by the NCX and possibly to a lesser extent, the PMCA. 10: Cytosolic Ca²⁺ is strongly buffered by Ca²⁺-binding proteins. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDAR, N-methyl-d-aspartate receptor; VGCC, voltage-gated Ca²⁺ channel; CICR, Ca²⁺-induced Ca²⁺ release; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase; SOC, store-operated channel; IP3R, inositol triphosphate receptor; NCX, Na⁺/Ca²⁺ exchanger; PMCA, plasma membrane Ca²⁺-ATPase.