Abstract
Regulation of ion and pH homeostasis is essential for normal neuronal function. The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pHi) and chloride concentration ([Cl−]i) in neurons. Here we show that NCBE is strongly expressed in the retina. As GABAA receptors conduct both chloride and bicarbonate, we hypothesized that NCBE may be relevant for GABAergic transmission in the retina. Importantly, we found a differential expression of NCBE in bipolar cells: whereas NCBE was expressed on ON and OFF bipolar cell axon terminals, it only localized to dendrites of OFF bipolar cells. On these compartments, NCBE colocalized with the main neuronal chloride extruder KCC2, which renders GABA hyperpolarizing. NCBE was also expressed in starburst amacrine cells, but was absent from neurons known to depolarize in response to GABA, like horizontal cells. Mice lacking NCBE showed decreased visual acuity and contrast sensitivity in behavioral experiments and smaller b-wave amplitudes and longer latencies in electroretinograms. Ganglion cells from NCBE-deficient mice also showed altered temporal response properties. In summary, our data suggest that NCBE may serve to maintain intracellular chloride and bicarbonate concentration in retinal neurons. Consequently, lack of NCBE in the retina may result in changes in pHi regulation and chloride-dependent inhibition, leading to altered signal transmission and impaired visual function.
Highlights
The vertebrate retina represents a neuronal tissue with a high metabolic rate
With markers for individual bipolar and amacrine cell types, we reveal a differential expression in ON and OFF bipolar cell compartments and starburst amacrine cells in which NCBE is colocalized with KCC2
Photoreceptors and their terminals were devoid of label (Fig. S1) whereas some cell membranes in the distal and proximal inner nuclear layer (INL) were stained for NCBE, presumably representing bipolar (Fig. 1C, arrows) and amacrine cell somata (Fig. 1C, arrowheads)
Summary
The vertebrate retina represents a neuronal tissue with a high metabolic rate. regulation of intracellular pH (pHi) is of vital importance because energy metabolism is a proton-producing process [1]. The sodium bicarbonate co-transporter NBCn1 contributes to pH regulation in photoreceptors and lack thereof causes blindness [4] as does a lack of the chloride bicarbonate anion exchanger AE3 which was shown to be expressed in Muller cells and horizontal cells [5,6]. In bipolar cell dendrites, differential expression of KCC2 and NKCC1 chloride transporters serves to generate GABA-evoked responses of different polarity [16]. To analyze the functional importance of NCBE, we used a NCBE-deficient mouse line [12] and show that lack of NCBE leads to altered retinal responses and impaired visual performance Whether these effects are caused by an altered pHi regulation of retinal neurons, by changes in the driving force for inhibitory currents or by a combination of both, remains to be seen
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