Carbonic anhydrase XIV deficiency produces a functional defect in the retinal light response

Abstract

Members of the carbonic anhydrase (CA) family play an important role in the regulation of pH, CO 2 , ion, and water transport. CA IV and CA XIV are membrane-bound isozymes expressed in the eye. CA IV immunostaining is limited to the choriocapillaris overlying the retina, whereas CA XIV is expressed within the retina in Müller glial cells and retinal pigment epithelium. Here, we have characterized the physiological and morphological phenotype of the CA IV-null, CA XIV-null, and CA IV/CA XIV-double-null mouse retinas. Flash electroretinograms performed at 2, 7, and 10 months of age showed that the rod/cone a-wave, b-wave, and cone b-wave were significantly reduced (26–45%) in the CA XIV-null mice compared with wild-type littermates. Reductions in the dark-adapted response were not progressive between 2 and 10 months, and no differences in retinal morphology were observed between wild-type and CA XIV-null mice. Müller cells and rod bipolar cells had a normal appearance. Retinas of CA IV-null mice showed no functional or morphological differences compared with normal littermates. However, CA IV/CA XIV double mutants showed a greater deficit in light response than the CA XIV-null retina. Our results indicate that CA XIV, which regulates extracellular pH and pCO 2 , plays an important part in producing a normal retinal light response. A larger functional deficit in the CA IV/CA XIV double mutants suggests that CA IV can also contribute to pH regulation, at least in the absence of CA XIV.

Bicarbonate homeostasis in excitable tissues: role of AE3 Cl−/HCO3− exchanger and carbonic anhydrase XIV interaction

“…A mouse deficient for caXIV (caXIV Ϫ/Ϫ ) has been recently described, with intriguing similarities to the phenotype of ae3 Ϫ/Ϫ mice (39). Flash ERGs performed at 2, 7, and 10 mo of age showed that the rod/cone a-wave, b-wave, and cone bwave were significantly reduced (up to 45%) in the caXIV Ϫ/Ϫ mice compared with its wild-type littermates (26). Thus, the phenotype was much milder than in the ae3 Ϫ/Ϫ -null mice, since transport by AE3 is still substantial without CAXIV (Fig.…”

Altered visual function in monocarboxylate transporter 3 (Slc16a8) knockout mice

“…pH homeostasis in the outer retina is maintained by the coordinated activities of electrogenic Na ϩ /HCO 3 Ϫ cotransporters, Na ϩ /H ϩ exchangers, Na ϩ /HCO 3 Ϫ exchangers, and carbonic anhydrases (CA). Mutations in genes that contribute to acid-base regulation in the retina are known to cause ocular phenotypes with varying degrees of severity (2,3,7,17,29). CA XIV is an integral membrane protein with an extracellular catalytic domain that is expressed in the apical processes of both Müller and RPE cells.…”

Pathogenesis of retinitis pigmentosa associated with apoptosis-inducing mutations in carbonic anhydrase IV

“…This defect had previously been attributed to disruption of the NBC1-CA IV metabolon function, either due to decreased physical interaction (R14W and R69H mutations) or due to altered catalytic activity of R219S CA IV (3,4). This loss of function theory, however, does not explain the dominant inheritance pattern of the disease or the absence of any retinal abnormality in the CA IV-knockout mouse (9).…”

“…However, this hypothesis does not adequately explain how loss of only 1 functional CA IV allele can cause retinal degeneration and lead to a dominant disease. Furthermore, lack of any retinal abnormality in the CA IV-knockout (KO) mice indicated that even total loss of CA IV function did not cause retinal disease in the mouse (9).…”