Abstract
The regulation of the acid-base balance in cells is essential for proper cellular homeostasis. Disturbed acid-base balance directly affects cellular physiology, which often results in various pathological conditions. In every living organism, the protein family of carbonic anhydrases regulate a broad variety of homeostatic processes. Here we describe the identification, mapping and cloning of a zebrafish carbonic anhydrase 5 (ca5) mutation, collapse of fins (cof), which causes initially a collapse of the medial fins followed by necrosis and rapid degeneration of the embryo. These phenotypical characteristics can be mimicked in wild-type embryos by acetazolamide treatment, suggesting that CA5 activity in zebrafish is essential for a proper development. In addition we show that CA5 regulates acid-base balance during embryonic development, since lowering the pH can compensate for the loss of CA5 activity. Identification of selective modulators of CA5 activity could have a major impact on the development of new therapeutics involved in the treatment of a variety of disorders.
Highlights
Maintaining proper homeostasis is essential for every living organism
We show that defective carbonic anhydrase 5 (CA5) activity in zebrafish results in a disturbed cellular acid-base balance, which leads to the collapse of the medial fins, heart failure and eventually degeneration of the complete embryo
We show that AZA, a general Carbonic anhydrases (CA) inhibitor, can copy the phenotype caused by the ca5cof mutation in wild-type embryos, suggesting that the T839A mutation results in the loss of CA5 enzymatic activity
Summary
Maintaining proper homeostasis is essential for every living organism. Homeostatic imbalance directly affects cellular metabolism, which eventually leads to physiological defects and pathologic conditions. Carbonic anhydrases (CA) are zinc metalloenzymes that are present in prokaryotes and eukaryotes. They catalyze the reversible dehydration/hydration reaction of carbon dioxide (CO2 + H2O « HCO32+ H+) [1,2]. CAs are involved in many physiological processes such as transport of carbon dioxide and bicarbonate between tissues, acid-base balance and biosynthetic reactions (glucogenesis, lipogenesis and ureagenesis) [3]. CAs are important therapeutic targets, because of their involvement in various pathological conditions, such as glaucoma, obesity, some infectious diseases, cancer, epilepsy and osteoporosis [4] many CA inhibitors and activators have been developed in order to treat these disorders [4]. We describe the mapping, cloning and characterization of a ca mutant zebrafish (collapse of fins, cof) and show that CA5 is involved in regulating acid-base balance during embryonic development in zebrafish
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