Lack of the sodium-driven chloride bicarbonate exchanger NCBE impairs visual function in the mouse retina.
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 (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons. Here we show that NCBE is strongly expressed in the retina. As GABA(A) 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 pH(i) regulation and chloride-dependent inhibition, leading to altered signal transmission and impaired visual function.
Department of Neurobiology, University Oldenburg, Oldenburg, Germany.
Gerrit
G
Hilgen
Antje K
AK
Huebner
Naoyuki
N
Tanimoto
Vithiyanjali
V
Sothilingam
Christina
C
Seide
Marina
M
Garcia Garrido
Karl-Friedrich
KF
Schmidt
Mathias W
MW
Seeliger
Siegrid
S
Löwel
Reto
R
Weiler
Christian A
CA
Hübner
Karin
K
Dedek
D025042:Amacrine Cells / Q000378:metabolism; D000818:Animals; D027963:Chloride-Bicarbonate Antiporters / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015350:Contrast Sensitivity / Q000235:genetics / Q000502:physiology; D004596:Electroretinography; D005724:Ganglia / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010775:Photic Stimulation; D012160:Retina / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051245:Retinal Bipolar Cells / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000502:physiology; D027982:Sodium-Bicarbonate Symporters / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D027981:Symporters / Q000378:metabolism; D014792:Visual Acuity / Q000235:genetics / Q000502:physiology*; D000096922:K Cl- Cotransporters
D027963:Chloride-Bicarbonate Antiporters; D027982:Sodium-Bicarbonate Symporters; D027981:Symporters; D000096922:K Cl- Cotransporters; C526208:Slc4a10 protein, mouse