The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

CA4  -  carbonic anhydrase IV

Homo sapiens

Synonyms: CA-IV, CAIV, Car4, Carbonate dehydratase IV, Carbonic anhydrase 4, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of CA4

  • Therefore, it is suggested that even moderate hypoxic injury induces astrocytosis in the CA3 and CA4 regions and may affect the neuronal proteins and the metabolism, and that in cases with a history of hypoxic attacks neuronal damage may be severe even several hours after ischemic injury [1].
  • Furthermore, CA IV is more active in HCO3- dehydration than is CA II as illustrated by the nearly 3-fold increase in kcat/K(M) to 3 x 10(7) M(-1) s(-1) [2].
  • Methods to evaluate patients with pure proximal renal tubular acidosis for deficiency of CA IV are also discussed [3].
  • In comparison with control brains, statistically significant decline of pyramidal cell density was found in hippocampal CA1 and CA4 sectors of acute hypoxia brains [4].
  • Serum antibodies to carbonic anhydrase IV in patients with autoimmune pancreatitis [5].

Psychiatry related information on CA4

  • A "net pathology" score combining standardized z-scores for synapse density and NFTs was significantly correlated with all three mental status measures in all hippocampal subregions except the entorhinal cortex, and stepwise regressions on these data found net pathology in CA4 to be the most independent significant predictor of premortem dementia [6].
  • We tested the hypothesis that there is differential expression of MnSOD in the CA1, CA2/3, and CA4 region of the hippocampus which may account for the neuronal loss seen in Alzheimer's disease [7].
  • Cellular GAD(65) mRNA expression was significantly decreased in subjects with bipolar disorder, particularly in CA4, but not in schizophrenic subjects [8].
  • Three of the four groups (treated and control adults and control old mice) did not differ from one another in task performance or neuron density in frontal cortex, cerebellum, dentate gyrus or CA1-2, CA3, CA4 hippocampal areas [9].
  • None of the cell density measures in the CA1 and CA4 subfields were significantly correlated with the preoperative neuropsychological test scores in the RTL group [10].

High impact information on CA4


Chemical compound and disease context of CA4

  • We have recently shown that renal cortical sodium dodecyl sulfate (SDS)-resistant hydratase (presumably CA IV) activity was stimulated 241% during chronic metabolic acidosis (CMA) [14].
  • The results suggest that the turnover of palmitate-containing lipids is retained in the CA1 pyramidal layer of the gerbil hippocampus for 1 day and then reduced at 3 days after 5-min ischemia and that lipid synthesis is stimulated in hippocampal regions affected by but recovering from an ischemic insult (CA3, CA4, dentate gyrus) [15].
  • EXPERIMENTAL DESIGN: C3H/HeJ mice bearing KHT sarcomas were treated with CA4P and OXi4503 and the effect on tumor vasculature was determined by evaluating the extent of vascular shutdown (Hoechst-33342 vessel staining) and tumor perfusion inhibition (dynamic contrast-enhanced magnetic resonance imaging) [16].
  • Thus, it was indicated that during the first 5 min of ischemia glutamate was released mostly from CA4 neurons but not from granule cells of the dentate gyrus [17].
  • A series of analogs with nitro or serinamide substituents at the C-2'-, C-5'-, or C-6'-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in SCID mice, and as inhibitors of tubulin polymerization [18].

Biological context of CA4


Anatomical context of CA4


Associations of CA4 with chemical compounds


Physical interactions of CA4

  • The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV [25].
  • Carbonic anhydrase IV (CA IV) is a membrane-bound form of carbonic anhydrase [2].
  • Here, we report the X-ray crystal structures of three novel thieno[3,2-e]-1,2-thiazine-6-sulfonamides complexed with CAII and the computationally predicted structures of the same compounds complexed with CAIV [26].
  • We have identified extracellular regions of AE1 and NBC1 that directly interact with CAIV, to form a physical complex between the proteins [27].

Regulatory relationships of CA4

  • Here we present experiments showing that several well characterized CA inhibitors largely prevent the adverse effects of expressing R14W CA IV in transfected COS-7 cells [20].
  • One day after ischemia-reperfusion, MCP-1 mRNA was clearly expressed in the CA4 subfield and the molecular layer of the dentate gyrus, while it was slightly expressed in the lacnosum moleculare of the CA1 subfield [28].
  • On the basis of these observations, we propose that the absence of CA IV in apical plasma membranes due to the impairment in targeting in cells expressing a deltaAF508 CFTR largely contributes to the disruption in HCO3- secretion in CF epithelia [29].

Other interactions of CA4

  • These studies indicate that the membrane-associated CA in human eye, which was suspected from histochemical studies, is CA IV [30].
  • CA IV activity and immunoreactivity were present in normal amounts in urinary membranes from CA II-deficient patients [23].
  • To determine whether cell surface-anchored carbonic anhydrase IV (CAIV) interacts with AE proteins to accelerate the bicarbonate transport rate, AE1-mediated bicarbonate transport was monitored in transfected HEK293 cells [25].
  • For CA I the new derivatives showed inhibition constants in the range of 3-12 nM, for CA II in the range of 0.20-5.96 nM, against CA IV in the range of 2.0-10.3 nM, and against CA IX in the range of 3-45 nM, respectively [31].
  • In addition, northern blot hybridisation was performed to assess expression of CA4, CA9, and CA12 mRNA in cultured NPE cells from normal and glaucoma donors [22].

Analytical, diagnostic and therapeutic context of CA4

  • Expression of the cDNA in COS cells produced a 35-kDa enzyme that was membrane associated, resistant to inactivation by SDS, contained no carbohydrate, and reacted on Western blots with antiserum to the 35-kDa CA IV from human lung [19].
  • Amino acid compositions of both lung and kidney CA IV were similar, as were tryptic peptide patterns resolved on high performance liquid chromatography (HPLC) [32].
  • SDS-PAGE followed by immunoblotting showed that the predominant portion of total muscle CA IV was bound in these complexes and therefore must be located intravascularly [33].
  • In the HS group, a small decrease in EAAT1-immunoreactivity (IR) was observed in CA4 and in the polymorphic and supragranular layer of the dentate gyrus, compared with the control group [34].
  • CA4P has completed Phase I clinical trials, but recent preclinical studies have shown that CA1P displays a greater antitumor effect than the combretastatin A4 (CA4) analog at equal doses [35].


  1. Immunohistochemical investigation of hypoxic/ischemic brain damage in forensic autopsy cases. Kitamura, O. Int. J. Legal Med. (1994) [Pubmed]
  2. Catalysis and inhibition of human carbonic anhydrase IV. Baird, T.T., Waheed, A., Okuyama, T., Sly, W.S., Fierke, C.A. Biochemistry (1997) [Pubmed]
  3. Evaluation of carbonic anhydrase isozymes in disorders involving osteopetrosis and/or renal tubular acidosis. Sly, W.S., Sato, S., Zhu, X.L. Clin. Biochem. (1991) [Pubmed]
  4. Quantitative studies of human newborns' hippocampal pyramidal cells after perinatal hypoxia. Kuchna, I. Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences. (1994) [Pubmed]
  5. Serum antibodies to carbonic anhydrase IV in patients with autoimmune pancreatitis. Nishimori, I., Miyaji, E., Morimoto, K., Nagao, K., Kamada, M., Onishi, S. Gut (2005) [Pubmed]
  6. Hippocampal connectivity and Alzheimer's dementia: effects of synapse loss and tangle frequency in a two-component model. Samuel, W., Masliah, E., Hill, L.R., Butters, N., Terry, R. Neurology (1994) [Pubmed]
  7. Differential neuronal expression of manganese superoxide dismutase in Alzheimer's disease. Marcus, D.L., Strafaci, J.A., Freedman, M.L. Med. Sci. Monit. (2006) [Pubmed]
  8. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Heckers, S., Stone, D., Walsh, J., Shick, J., Koul, P., Benes, F.M. Arch. Gen. Psychiatry (2002) [Pubmed]
  9. Effect of chronic treatment with recombinant interleukin-2 on the central nervous system of adult and old mice. Nemni, R., Iannaccone, S., Quattrini, A., Smirne, S., Sessa, M., Lodi, M., Erminio, C., Canal, N. Brain Res. (1992) [Pubmed]
  10. Hippocampal cell loss and gliosis: relationship to preoperative and postoperative memory function. Baxendale, S.A., Van Paesschen, W., Thompson, P.J., Duncan, J.S., Harkness, W.F., Shorvon, S.D. Neuropsychiatry, neuropsychology, and behavioral neurology. (1998) [Pubmed]
  11. Human carbonic anhydrases and carbonic anhydrase deficiencies. Sly, W.S., Hu, P.Y. Annu. Rev. Biochem. (1995) [Pubmed]
  12. Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. Vincent, L., Kermani, P., Young, L.M., Cheng, J., Zhang, F., Shido, K., Lam, G., Bompais-Vincent, H., Zhu, Z., Hicklin, D.J., Bohlen, P., Chaplin, D.J., May, C., Rafii, S. J. Clin. Invest. (2005) [Pubmed]
  13. Carbonic anhydrase IV expression in rat and human gastrointestinal tract regional, cellular, and subcellular localization. Fleming, R.E., Parkkila, S., Parkkila, A.K., Rajaniemi, H., Waheed, A., Sly, W.S. J. Clin. Invest. (1995) [Pubmed]
  14. Expression of carbonic anhydrase IV mRNA in rabbit kidney: stimulation by metabolic acidosis. Winkler, C.A., Kittelberger, A.M., Schwartz, G.J. Am. J. Physiol. (1997) [Pubmed]
  15. Regional [14C]palmitate incorporation into the hippocampus after transient cerebral ischemia in awake gerbils. Tone, O., Matsushima, Y., Inaba, Y., Rapoport, S.I. Advances in neurology. (1990) [Pubmed]
  16. Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity. Salmon, H.W., Siemann, D.W. Clin. Cancer Res. (2006) [Pubmed]
  17. Ischemia-induced glutamate release in the dentate gyrus. A microdialysis study in the gerbil. Cui, Y., Zhang, L., Utsunomiya, K., Yanase, H., Mitani, A., Kataoka, K. Neurosci. Lett. (1999) [Pubmed]
  18. Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents. Monk, K.A., Siles, R., Hadimani, M.B., Mugabe, B.E., Ackley, J.F., Studerus, S.W., Edvardsen, K., Trawick, M.L., Garner, C.M., Rhodes, M.R., Pettit, G.R., Pinney, K.G. Bioorg. Med. Chem. (2006) [Pubmed]
  19. Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression in COS cell membranes. Okuyama, T., Sato, S., Zhu, X.L., Waheed, A., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  20. Chemical chaperones protect from effects of apoptosis-inducing mutation in carbonic anhydrase IV identified in retinitis pigmentosa 17. Bonapace, G., Waheed, A., Shah, G.N., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  21. Gene expression for carbonic anhydrase isoenzymes in human nasal mucosa. Tarun, A.S., Bryant, B., Zhai, W., Solomon, C., Shusterman, D. Chem. Senses (2003) [Pubmed]
  22. Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma. Liao, S.Y., Ivanov, S., Ivanova, A., Ghosh, S., Cote, M.A., Keefe, K., Coca-Prados, M., Stanbridge, E.J., Lerman, M.I. J. Med. Genet. (2003) [Pubmed]
  23. Carbonic anhydrase isozymes IV and II in urinary membranes from carbonic anhydrase II-deficient patients. Sato, S., Zhu, X.L., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  24. Membrane-bound carbonic anhydrase IV is expressed in the luminal plasma membrane of the human gallbladder epithelium. Parkkila, S., Parkkila, A.K., Juvonen, T., Waheed, A., Sly, W.S., Saarnio, J., Kaunisto, K., Kellokumpu, S., Rajaniemi, H. Hepatology (1996) [Pubmed]
  25. The extracellular component of a transport metabolon. Extracellular loop 4 of the human AE1 Cl-/HCO3- exchanger binds carbonic anhydrase IV. Sterling, D., Alvarez, B.V., Casey, J.R. J. Biol. Chem. (2002) [Pubmed]
  26. Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV. Kim, C.Y., Whittington, D.A., Chang, J.S., Liao, J., May, J.A., Christianson, D.W. J. Med. Chem. (2002) [Pubmed]
  27. The bicarbonate transport metabolon. McMurtrie, H.L., Cleary, H.J., Alvarez, B.V., Loiselle, F.B., Sterling, D., Morgan, P.E., Johnson, D.E., Casey, J.R. Journal of enzyme inhibition and medicinal chemistry. (2004) [Pubmed]
  28. Expression of MCP-1 in the Hippocampus of SHRSP with Ischemia-Related Delayed Neuronal Death. Sakurai-Yamashita, Y., Shigematsu, K., Yamashita, K., Niwa, M. Cell. Mol. Neurobiol. (2006) [Pubmed]
  29. Targeting of carbonic anhydrase IV to plasma membranes is altered in cultured human pancreatic duct cells expressing a mutated (deltaF508) CFTR. Fanjul, M., Salvador, C., Alvarez, L., Cantet, S., Hollande, E. Eur. J. Cell Biol. (2002) [Pubmed]
  30. Localization of carbonic anhydrase IV in a specific capillary bed of the human eye. Hageman, G.S., Zhu, X.L., Waheed, A., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  31. Carbonic anhydrase inhibitors. Design of selective, membrane-impermeant inhibitors targeting the human tumor-associated isozyme IX. Casey, J.R., Morgan, P.E., Vullo, D., Scozzafava, A., Mastrolorenzo, A., Supuran, C.T. J. Med. Chem. (2004) [Pubmed]
  32. Carbonic anhydrase IV from human lung. Purification, characterization, and comparison with membrane carbonic anhydrase from human kidney. Zhu, X.L., Sly, W.S. J. Biol. Chem. (1990) [Pubmed]
  33. Immunohistochemical localization of carbonic anhydrase IV in capillaries of rat and human skeletal muscle. Sender, S., Gros, G., Waheed, A., Hageman, G.S., Sly, W.S. J. Histochem. Cytochem. (1994) [Pubmed]
  34. Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Proper, E.A., Hoogland, G., Kappen, S.M., Jansen, G.H., Rensen, M.G., Schrama, L.H., van Veelen, C.W., van Rijen, P.C., van Nieuwenhuizen, O., Gispen, W.H., de Graan, P.N. Brain (2002) [Pubmed]
  35. Comparative preclinical pharmacokinetic and metabolic studies of the combretastatin prodrugs combretastatin A4 phosphate and A1 phosphate. Kirwan, I.G., Loadman, P.M., Swaine, D.J., Anthoney, D.A., Pettit, G.R., Lippert, J.W., Shnyder, S.D., Cooper, P.A., Bibby, M.C. Clin. Cancer Res. (2004) [Pubmed]
WikiGenes - Universities