Affinage

CA2

Carbonic anhydrase 2 · UniProt P00918

Round 2 corrected
Length
260 aa
Mass
29.2 kDa
Annotated
2026-04-28
130 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CA2 encodes carbonic anhydrase II, the most catalytically efficient cytoplasmic zinc metalloenzyme among carbonic anhydrase isozymes, catalyzing reversible hydration of CO2 to bicarbonate via a zinc-bound hydroxide mechanism in which intramolecular proton transfer from the zinc-water to His64 through an ordered solvent network constitutes the rate-limiting step (PMID:7574487, PMID:17319692). The active site zinc is tetrahedrally coordinated by His94, His96, His119, and a water/hydroxide molecule, with Thr199 and Glu106 forming a hydrogen-bond network essential for catalysis (PMID:3151019). CA2 directly binds the cytoplasmic tails of the Cl⁻/HCO₃⁻ exchanger AE1 (via the D887ADD motif) and the Na⁺/H⁺ exchanger NHE1, forming transport metabolons that potentiate bicarbonate and proton flux across membranes (PMID:9774471, PMID:11606574, PMID:12138085). Loss-of-function mutations in CA2 cause an autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification (PMID:3925334, PMID:12566520).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1972 High

    Determination of the first crystal structure of human CA II revealed the zinc-containing active site and overall protein fold, establishing the structural framework for all subsequent mechanistic studies.

    Evidence X-ray crystallography of human carbonic anhydrase C

    PMID:4621826

    Open questions at the time
    • Resolution insufficient to define hydrogen-bond network or solvent structure
    • Active-site mechanism and catalytic cycle not yet elucidated
  2. 1985 High

    Demonstration that CA II enzymatic activity and protein are virtually absent in patients with osteopetrosis, renal tubular acidosis, and cerebral calcification established CA2 loss-of-function as the molecular basis of this autosomal recessive syndrome, linking the enzyme to bone resorption and renal acid-base homeostasis.

    Evidence HPLC, CO2 hydratase/esterase activity assays, and immunoprecipitation of erythrocyte hemolysates from 18 patients in 11 families

    PMID:3925334

    Open questions at the time
    • Whether the bone and kidney phenotypes arise from a single common mechanism or separate tissue-specific functions was unclear
    • Specific causative mutations not yet identified at the DNA level in most families
  3. 1988 High

    High-resolution refinement of the CA II structure resolved the tetrahedral zinc coordination (His94, His96, His119, water) and the Thr199–Glu106 hydrogen-bond relay, defining the catalytic geometry, while inhibitor co-crystal structures established that sulfonamides coordinate zinc via the sulfonamide nitrogen and that alternative zinc coordination geometries are possible.

    Evidence X-ray crystallography at 2.0 Å (apo) and 1.9–3.1 Å (inhibitor complexes)

    PMID:3151019 PMID:3151020

    Open questions at the time
    • Proton-transfer pathway and rate-limiting step not yet defined
    • Solvent network in the active site not resolved at this resolution
  4. 1995 High

    Systematic kinetic and mutagenesis studies consolidated the zinc-bound hydroxide mechanism and identified CA II as the most catalytically efficient CA isozyme, framing subsequent work on the proton shuttle.

    Evidence Review synthesizing recombinant wild-type and mutant CA kinetics, inhibitor studies, and CA-deficient animal/human data

    PMID:7574487

    Open questions at the time
    • Atomic-resolution definition of the proton-transfer solvent bridge remained outstanding
    • Role of His64 conformational dynamics not directly observed
  5. 1998 High

    Discovery that CA II binds directly to the C-terminal cytoplasmic tail of the Cl⁻/HCO₃⁻ exchanger AE1 with nanomolar affinity introduced the concept that CA II participates in membrane transport by physical association with ion transporters.

    Evidence Co-immunoprecipitation from ghost membranes, solid-phase binding assays, affinity chromatography, and immunofluorescence clustering

    PMID:9774471

    Open questions at the time
    • Functional consequence of the CA II–AE1 interaction on transport activity not yet tested
    • Binding determinants on AE1 not yet mapped
  6. 2000 High

    Mapping the CA II binding site on AE1 to the acidic motif D887ADD, with mutagenesis showing that acidic residues are essential, defined the molecular determinants of the CA II–transporter interaction.

    Evidence Peptide competition and point-mutant GST-fusion binding assays with immobilized CA II

    PMID:10820026

    Open questions at the time
    • No structure of the CA II–AE1 peptide complex
    • Reciprocal mapping of the binding surface on CA II not performed
  7. 2001 High

    Functional demonstration that CA II binding to AE1 potentiates Cl⁻/HCO₃⁻ exchange activity—using CA inhibitors, binding-deficient AE1 mutants, and dominant-negative CA II—established the 'transport metabolon' concept wherein substrate channeling between enzyme and transporter accelerates transmembrane bicarbonate flux.

    Evidence Intracellular pH-based anion exchange assay in transfected HEK293 cells with multiple perturbations

    PMID:11606574

    Open questions at the time
    • Whether physical tethering alone or catalytic activity at the membrane interface drives the enhancement was not fully resolved
    • In vivo physiological confirmation in tissue lacking
  8. 2002 High

    Extension of the metabolon concept to NHE1 showed that CA II also binds NHE1's C-terminal region and enhances Na⁺/H⁺ exchange, with phosphorylation of NHE1 greatly increasing CA II binding, revealing a regulated partnership.

    Evidence Microtiter plate binding, affinity blotting, co-IP from CHO cells, pH-based transport assays, dominant-negative CA II, phosphorylation studies

    PMID:12138085

    Open questions at the time
    • Kinase(s) responsible for the phosphorylation-dependent regulation not identified
    • Structural basis of phospho-dependent enhancement unknown
  9. 2003 Medium

    Identification of a novel CA2 frameshift mutation in a family with osteopetrosis plus renal tubular acidosis, alongside the finding that co-inheritance of TCIRG1 and ATP6V1B1 mutations can phenocopy CA II deficiency, mechanistically separated the bone and kidney acid-secretion pathways downstream of CA II.

    Evidence Molecular genetic sequencing, homozygosity mapping, and CA II protein quantification in two kindreds

    PMID:12566520

    Open questions at the time
    • Small number of families limits generalizability
    • Relative contribution of CA II to osteoclast versus renal intercalated cell H⁺ secretion not quantified
  10. 2007 High

    An ultra-high-resolution (1.05 Å) crystal structure combined with molecular dynamics defined the His64 dual conformation and the ordered solvent network mediating proton transfer from zinc-bound water to His64, establishing the rate-limiting proton shuttle as the mechanistic basis for CA II's extraordinary catalytic turnover.

    Evidence X-ray crystallography at 1.05 Å with anisotropic B-factor analysis cross-validated by MD simulation

    PMID:17319692

    Open questions at the time
    • Direct experimental observation of proton transfer dynamics (e.g., neutron diffraction, time-resolved methods) not yet achieved at that time
    • Contribution of individual water molecules in the relay not individually tested by mutagenesis
  11. 2009 High

    Discovery that coumarins inhibit CA II through a suicide mechanism—hydrolysis to cis-2-hydroxy-cinnamic acid that occludes the active-site entrance without zinc coordination—revealed a fundamentally distinct inhibition mode from classical sulfonamides, expanding the pharmacological toolkit.

    Evidence X-ray crystallography of the CA II–coumarin adduct and enzyme kinetics across 13 mammalian CA isoforms

    PMID:19206230

    Open questions at the time
    • Selectivity profile of coumarins among CA isoforms not fully optimized
    • In vivo efficacy data for coumarin-class inhibitors limited
  12. 2019 Medium

    Demonstration that CA II is upregulated in tumor endothelial cells via VEGF-A/VEGFR signaling and that it promotes survival under lactic acidosis, with acetazolamide reducing metastasis in vivo, extended CA II's physiological role to pH homeostasis in the tumor microenvironment.

    Evidence siRNA knockdown, VEGF treatment, xenograft mouse models with acetazolamide, immunohistochemistry

    PMID:31847904

    Open questions at the time
    • Single-lab study; independent replication needed
    • Whether the anti-metastatic effect is CA II-specific or reflects pan-CA inhibition by acetazolamide is unresolved
    • Molecular mechanism linking CA II to endothelial cell survival under acidosis not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the CA II–transporter metabolon (no co-crystal structure of CA II bound to AE1 or NHE1 cytoplasmic domains), the identity of kinases regulating the CA II–NHE1 interaction, direct visualization of proton-transfer dynamics in real time, and whether CA II has non-catalytic scaffolding functions independent of its enzymatic activity.
  • No co-crystal structure of the CA II–transporter complex
  • Kinases phosphorylating NHE1 to enhance CA II binding unidentified
  • In vivo tissue-specific functions beyond erythrocytes and kidney not systematically characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0016829 lyase activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-1430728 Metabolism 3
Partners
SLC4A1SLC9A1

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1972 The crystal structure of human carbonic anhydrase II (CA II, then called carbonic anhydrase C) was determined, revealing a zinc ion in the active site coordinated by three histidine residues and establishing the enzyme's overall fold. X-ray crystallography Nature: New biology High 4621826
1988 Refined 2.0 Å crystal structure of human CA II showed the zinc ion coordinated tetrahedrally to three histidyl residues (His94, His96, His119) and one water molecule; Thr-199 donates a proton to Glu-106 and acts as a hydrogen-bond acceptor in the active site, clarifying hydrogen-bond donor-acceptor relations critical for catalysis. Constrained and restrained structure-factor least-squares X-ray crystallographic refinement at 2.0 Å Proteins High 3151019
1988 X-ray crystallographic studies of CA II inhibitor complexes showed: (1) sulfonamide inhibitors (AMS, acetazolamide) bind via the sulfonamide nitrogen to the zinc, retaining tetrahedral zinc geometry; (2) at high pH, thiocyanate forms a pentacoordinated zinc complex with both SCN- and a water molecule bound to zinc plus three histidines; (3) mercury binds at His-64 and Cys-206. These structures defined three possible zinc coordination geometries and informed the catalytic and inhibition mechanisms. X-ray crystallography of inhibitor-bound CA II complexes at 1.9–3.1 Å resolution Proteins High 3151020
1985 Virtual absence of carbonic anhydrase II (CAII) enzymatic activity (CO2 hydratase and esterase) and immunoprecipitable CAII protein was demonstrated in erythrocyte hemolysates from 18 patients in 11 families with the autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification, establishing CAII deficiency as the biochemical basis of this syndrome. High-performance liquid chromatography, enzyme activity assays (CO2 hydratase, esterase), immunoprecipitation of erythrocyte hemolysates The New England journal of medicine High 3925334
1992 v-erbA oncogene acts as a constitutive transcriptional repressor of the carbonic anhydrase II (CAII) gene in erythroblasts; reintroduction of CAII via retroviral vectors into v-erbA-transformed erythroblasts restored normal pH/ion tolerance of the cells, demonstrating that CAII expression is required for erythroblast pH homeostasis but does not reverse the v-erbA-induced differentiation block. Retroviral gene transfer of CAII into transformed erythroblasts, cell growth assays across pH/ionic-strength gradients The EMBO journal Medium 1354613
1995 Comprehensive review establishing that CA II is cytoplasmic, the most catalytically active carbonic anhydrase isozyme (highest kcat/Km for CO2 hydration), and that structural/kinetic studies of recombinant wild-type and mutant CA II have defined the structural requirements for catalysis, including the zinc-bound hydroxide mechanism. Review synthesizing kinetic studies of recombinant natural and mutant CAs, inhibitor studies, and CA-deficient animal/human data Annual review of biochemistry High 7574487
1998 CA II binds directly to the 33-residue carboxyl-terminal (Ct) region of the erythrocyte Cl-/HCO3- exchanger band 3 (AE1) with K1/2 ~20–100 nM; the interaction was demonstrated by co-immunoprecipitation from ghost membranes, co-solubilization, solid-phase binding assays with GST-Ct fusion proteins, and affinity chromatography showing 1:1 stoichiometry. Clustering of band 3 in membranes caused co-clustering of CAII, indicating an in situ physical association. Co-immunoprecipitation, co-solubilization, solid-phase binding assay, affinity chromatography, immunofluorescence clustering The Journal of biological chemistry High 9774471
2000 The CA II binding site on AE1 was mapped to residues 887–890 (D887ADD) within the carboxyl-terminal 33-residue region; mutation of D887ADD to AAAA or NANN abolished CAII binding, while mutation to D887ANE (the homologous AE2 sequence) retained binding, identifying acidic residues at this motif as critical for CA II tethering to the anion exchanger. Peptide competition assays, truncation and point mutant GST-fusion protein binding assays (microtiter plate binding assay) with immobilized CAII Biochemistry High 10820026
2001 CA II forms a 'transport metabolon' with AE1 (and AE2, AE3 cardiac isoforms): inhibition of endogenous CA with acetazolamide reduced AE1-mediated Cl-/HCO3- exchange by 50–60% in HEK293 cells; AE1 mutants unable to bind CAII retained only ~10% of wild-type transport activity; displacement of endogenous CAII by a functionally inactive dominant-negative mutant (V143Y) inhibited AE1 activity by ~61%, demonstrating that direct CAII binding to AE1 potentiates anion transport activity. Intracellular pH-based anion exchange assay in transfected HEK293 cells, dominant-negative CAII co-transfection, CA inhibitor (acetazolamide) treatment, AE1 CAII-binding mutants The Journal of biological chemistry High 11606574
2002 CA II binds to the C-terminal region of the Na+/H+ exchanger NHE1 (demonstrated by microtiter plate binding assay, affinity blotting, and co-immunoprecipitation from CHO cells); CAII binding enhances NHE1 H+ transport rate ~2-fold; acetazolamide (CA inhibitor) and dominant-negative CAII both reduced NHE1 activity; phosphorylation of the NHE1 C-terminus greatly increased CAII binding, suggesting phosphorylation-dependent modulation of CAII–NHE1 interaction. Microtiter plate binding assay, affinity blotting, co-immunoprecipitation from CHO cells, intracellular pH-based transport assays, dominant-negative CAII, phosphorylation studies The Journal of biological chemistry High 12138085
2003 A novel frameshift mutation in CA2 was identified in a consanguineous kindred with osteopetrosis and distal renal tubular acidosis (dRTA), confirming loss-of-function of CAII as causative; in a second kindred with identical clinical phenotype, CAII levels were normal, revealing that co-inheritance of mutations in TCIRG1 (osteoclast H+-ATPase subunit a) and ATP6V1B1 (kidney H+-ATPase B1 subunit) can phenocopy CAII deficiency, mechanistically separating the bone and kidney components. Molecular genetic analysis (sequencing, homozygosity mapping), CAII protein quantification, gene exclusion studies Journal of medical genetics Medium 12566520
2004 Celecoxib and valdecoxib (COX-2-selective NSAIDs bearing arylsulfonamide groups) inhibit CA II with nanomolar affinity; X-ray crystal structure of the celecoxib–CA II complex showed the sulfonamide nitrogen coordinates the catalytic zinc ion, while the trifluoromethylphenyl ring occupies the hydrophobic half of the active site, demonstrating an unexpected cross-reactivity that lowers intraocular pressure in glaucomatous rabbits. Enzyme kinetics (CO2 hydratase assay), X-ray crystallography of CA II–celecoxib complex, in vivo intraocular pressure measurement Journal of medicinal chemistry High 14736236
2005 Coumarins are suicide inhibitors of CA II: X-ray crystal structure of the CA II–coumarin complex revealed that the coumarin is hydrolyzed in the active site to a cis-2-hydroxy-cinnamic acid derivative, which plugs the entrance to the active site through interactions with Phe131, Asn67, and Glu238 without coordinating the zinc ion—representing a novel, non-zinc-mediated inhibition mechanism distinct from classical sulfonamide inhibitors. X-ray crystallography of CA II–coumarin adduct, enzyme kinetics (inhibition of all 13 mammalian CA isoforms), time-dependent inhibition assays Journal of the American Chemical Society High 19206230
2005 Zonisamide (antiepileptic drug) is a potent time-dependent inhibitor of CA II (Ki = 35.2 nM after 1-h incubation, vs. apparent 10.3 µM at 15 min); X-ray crystal structure at 1.70 Å showed the sulfonamide moiety coordinates the zinc ion via classic interactions with Thr199 and Glu106, while the benzisoxazole ring makes extensive van der Waals interactions with hydrophobic residues (Gln92, Val121, Phe131, Leu198, Thr200, Pro202). Enzyme kinetics (time-dependent CO2 hydrase inhibition assay), X-ray crystallography at 1.70 Å Bioorganic & medicinal chemistry letters High 15837316
2007 Ultra-high resolution (1.05 Å) X-ray crystal structure of unliganded CA II combined with molecular dynamics (MD) simulations revealed: (1) His64 adopts a dual conformation (inward/outward, ~80% inward); (2) a specific solvent network including water molecule W2 is positioned for proton relay between Zn-bound water and His64; (3) comparison of crystallographic anisotropic B-factors with MD root-mean-square fluctuations showed excellent agreement, supporting a proton-transfer mechanism via the solvent bridge to His64 as rate-limiting step. X-ray crystallography at 1.05 Å resolution (Rcryst 12.0%, Rfree 15.1%), molecular dynamics simulation Biochemistry High 17319692
2009 The dissociation constant of ethoxzolamide binding to human CA II was determined to be ~2 nM by displacement isothermal titration calorimetry (ITC) and thermal shift assay (TSA); ligand binding stabilized CA II by >10°C in Tm, and two separate melting transitions (ligand-free and ligand-bound fractions) were observed, validating combined ITC/TSA as a method for measuring tight CA II–inhibitor interactions. Displacement isothermal titration calorimetry (ITC), thermal shift assay (TSA), analysis of melting temperature dependence on protein and ligand concentrations International journal of molecular sciences Medium 19582223
2011 Simple inorganic anions (including azide, cyanate, cyanide, thiocyanate, bisulfite, nitrate, nitrite, iodide, and others) inhibit CA II through diverse mechanisms: some coordinate the zinc directly (e.g., thiocyanate, azide forming pentacoordinate zinc), while others bind in the active site without direct zinc coordination, providing structural and mechanistic insight into enzyme inhibition and the catalytic zinc environment. Enzyme kinetics (CO2 hydrase inhibition assays), review of X-ray crystallographic structures of anion-CA II complexes Journal of inorganic biochemistry High 22192857
1984 CA II is expressed in Müller glial cells of the mature chicken and mouse retina; during embryonic development CA II is first expressed broadly in all retinoblasts, then becomes restricted to Müller cells (and transiently to amacrine neurons), suggesting CA II has a role in glial support functions; comparative analysis across vertebrates revealed species-specific CA II distribution in horizontal cells and amacrine neurons. Immunohistochemistry with polyclonal and monoclonal antibodies to CA II in vertebrate retinas across developmental stages Annals of the New York Academy of Sciences Medium 6430181
1992 In CA II-deficient mice, membrane-associated carbonic anhydrase (CA) activity was preserved along the nephron (proximal tubule apical and basolateral membranes, thin limb, thick limb, distal tubule basolateral membranes), while cytoplasmic CA II staining was absent, demonstrating that membrane-bound CA isoforms (distinct from CA II) mediate transepithelial ion transport in renal tubules; in collecting duct, Type A intercalated cells showed apical membrane CA activity and Type B showed basolateral, consistent with their respective directions of H+ secretion. Immunocytochemistry (CA II) and cobalt-phosphate CA histochemistry in CA II-deficient and control mouse kidneys The journal of histochemistry and cytochemistry Medium 1431055
1994 In CA II-deficient mouse eyes, intense membrane-associated CA activity was preserved at apical and basolateral membranes of ciliary (pigmented and non-pigmented) epithelium, corneal endothelium, retinal pigment epithelium, Müller cells, lens epithelium, and choroidal/retinal capillary endothelium, demonstrating that membrane CA isoforms (not CA II) underlie transepithelial fluid and ion transport in the eye; inhibition of basolateral membrane CA of non-pigmented ciliary epithelium is proposed to explain aqueous humor reduction by CA inhibitors. Cobalt-phosphate CA histochemistry in CA II-deficient and normal mouse eyes Investigative ophthalmology & visual science Medium 8163345
2019 CA II (CAII) is upregulated in tumor endothelial cells (TECs) compared to normal endothelial cells both in vitro and in vivo; CAII knockdown decreased TEC survival specifically under lactic acidosis conditions; VEGF-A/VEGFR signaling induced CAII expression in normal endothelial cells; pharmacological CA inhibition with acetazolamide reduced lung metastasis in xenograft models, establishing CAII as a pH-regulatory survival factor in the tumor microenvironment. siRNA knockdown, Western blot, ELISA, cell proliferation (MTS assay), VEGF treatment, xenograft mouse models with acetazolamide treatment, immunohistochemistry Cell communication and signaling : CCS Medium 31847904

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Current biology : CB 1801 16005298
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
1995 Human carbonic anhydrases and carbonic anhydrase deficiencies. Annual review of biochemistry 667 7574487
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Genome-scale RNAi screen for host factors required for HIV replication. Cell host & microbe 627 18976975
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1988 Refined structure of human carbonic anhydrase II at 2.0 A resolution. Proteins 438 3151019
2009 Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors. Journal of the American Chemical Society 425 19206230
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Calcineurin inhibits VCX1-dependent H+/Ca2+ exchange and induces Ca2+ ATPases in Saccharomyces cerevisiae. Molecular and cellular biology 379 8628289
1972 Crystal structure of human carbonic anhydrase C. Nature: New biology 358 4621826
2000 CDPKs - a kinase for every Ca2+ signal? Trends in plant science 348 10740296
2004 Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition. Journal of medicinal chemistry 338 14736236
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
1994 Effects of rapid buffers on Ca2+ diffusion and Ca2+ oscillations. Biophysical journal 305 7919018
2001 A transport metabolon. Functional interaction of carbonic anhydrase II and chloride/bicarbonate exchangers. The Journal of biological chemistry 296 11606574
2007 Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport. The Biochemical journal 294 17716241
2020 Phosphorylated tau interactome in the human Alzheimer's disease brain. Brain : a journal of neurology 290 32812023
1985 Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. The New England journal of medicine 253 3925334
1990 Glutamate receptors activate Ca2+ mobilization and Ca2+ influx into astrocytes. Proceedings of the National Academy of Sciences of the United States of America 237 1970637
2015 La-related Protein 1 (LARP1) Represses Terminal Oligopyrimidine (TOP) mRNA Translation Downstream of mTOR Complex 1 (mTORC1). The Journal of biological chemistry 213 25940091
1985 Ca2+-dependent and Ca2+-independent phagocytosis in human neutrophils. Nature 202 3158824
1998 Carbonic anhydrase II binds to the carboxyl terminus of human band 3, the erythrocyte C1-/HCO3- exchanger. The Journal of biological chemistry 199 9774471
2013 Genome-wide association study identifies loci affecting blood copper, selenium and zinc. Human molecular genetics 197 23720494
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
1993 Regulation by Ca2+ in the Yersinia low-Ca2+ response. Molecular microbiology 177 8361348
2011 (In)organic anions as carbonic anhydrase inhibitors. Journal of inorganic biochemistry 169 22192857
2002 Carbonic anhydrase II binds to and enhances activity of the Na+/H+ exchanger. The Journal of biological chemistry 164 12138085
2005 Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies. Bioorganic & medicinal chemistry letters 159 15837316
1989 Caffeine-induced Ca2+ release activates Ca2+ extrusion via Na+-Ca2+ exchanger in cardiac myocytes. The American journal of physiology 155 2750887
1988 Crystallographic studies of inhibitor binding sites in human carbonic anhydrase II: a pentacoordinated binding of the SCN- ion to the zinc at high pH. Proteins 152 3151020
2000 Identification of the carbonic anhydrase II binding site in the Cl(-)/HCO(3)(-) anion exchanger AE1. Biochemistry 144 10820026
2007 Atomic crystal and molecular dynamics simulation structures of human carbonic anhydrase II: insights into the proton transfer mechanism. Biochemistry 143 17319692
2008 NAADP: a universal Ca2+ trigger. Science signaling 140 18984909
1996 Arachidonic acid activates the noncapacitative entry of Ca2+ during [Ca2+]i oscillations. The Journal of biological chemistry 139 8702966
1998 Inositol trisphosphate receptors: Ca2+-modulated intracellular Ca2+ channels. Biochimica et biophysica acta 130 9838027
2006 Ca2+ shuttling between endoplasmic reticulum and mitochondria underlying Ca2+ oscillations. EMBO reports 128 16415789
1993 CAR2, a prestalk cAMP receptor required for normal tip formation and late development of Dictyostelium discoideum. Genes & development 125 8436297
1990 Interaction of ruthenium red with Ca2(+)-binding proteins. Analytical biochemistry 125 1699445
1990 Ca2(+)-induced conformational change and aggregation of chromogranin A. The Journal of biological chemistry 122 2387861
2006 Ca2+-dependent rapid Ca2+ sensitization of contraction in arterial smooth muscle. Circulation research 121 17158339
1996 Ca2+ signaling and intracellular Ca2+ binding proteins. Journal of biochemistry 117 8947828
2007 Ca2+ stores regulate ryanodine receptor Ca2+ release channels via luminal and cytosolic Ca2+ sites. Biophysical journal 113 17351009
2003 Molecular determinants of Na+/Ca2+ exchange (NCX1) inhibition by SEA0400. The Journal of biological chemistry 109 14660663
2003 Function of caveolae in Ca2+ entry and Ca2+-dependent signal transduction. Traffic (Copenhagen, Denmark) 108 14617355
2005 Endogenous Ca2+ buffer concentration and Ca2+ microdomains in hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 97 15659591
2003 Epithelial Ca2+ entry channels: transcellular Ca2+ transport and beyond. The Journal of physiology 94 12869611
1993 Colocalization of active KCa channels and Ca2+ channels within Ca2+ domains in helix neurons. Neuron 93 8386529
1988 Two Ca2+-dependent ATPases in rat liver plasma membrane. The previously purified (Ca2+-Mg2+)-ATPase is not a Ca2+-pump but an ecto-ATPase. The Journal of biological chemistry 89 2457581
2011 Ca2+-dependent modulation of voltage-gated Ca2+ channels. Biochimica et biophysica acta 87 22223119
1994 Properties of intracellular Ca2+ waves generated by a model based on Ca(2+)-induced Ca2+ release. Biophysical journal 83 7696462
2003 Mitochondrial Ca2+ uptake requires sustained Ca2+ release from the endoplasmic reticulum. The Journal of biological chemistry 80 12586823
1996 Stimulation of the Na+/Ca2+ exchanger by phenylephrine, angiotensin II and endothelin 1. Journal of molecular and cellular cardiology 80 8745210
2009 Compartmentalized signalling: Ca2+ compartments, microdomains and the many facets of Ca2+ signalling. The FEBS journal 78 19243429
2014 Evolution of acidic Ca²⁺ stores and their resident Ca²⁺-permeable channels. Cell calcium 77 25591931
2003 A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. Journal of medical genetics 74 12566520
1986 Role of Ca2+ and Ca2+-activated protease in myoblast fusion. Experimental cell research 74 3002822
2006 Topics on the Na+/Ca2+ exchanger: pharmacological characterization of Na+/Ca2+ exchanger inhibitors. Journal of pharmacological sciences 69 16990699
1992 Two roles of Ca2+ in agonist stimulated Ca2+ oscillations. Biophysical journal 66 1324019
1990 Mode of action of alpha-latrotoxin: role of divalent cations in Ca2(+)-dependent and Ca2(+)-independent effects mediated by the toxin. Molecular pharmacology 66 2174508
1990 Ca2(+)-induced Ca2+ release as examined by photolysis of caged Ca2+ in single ventricular myocytes. The American journal of physiology 65 2301565
2005 Presynaptic Ca2+ dynamics, Ca2+ buffers and synaptic efficacy. Cell calcium 61 15820398
2000 Effects of the immunosuppressant FK506 on intracellular Ca2+ release and Ca2+ accumulation mechanisms. The Journal of physiology 61 10856121
1989 Relationship between cytosolic free Ca2+ and Na+-Ca2+ exchange in aortic muscle cells. The American journal of physiology 59 2912132
2009 Di(2-ethylhexyl) phthalate is a highly potent agonist for the human constitutive androstane receptor splice variant CAR2. Molecular pharmacology 58 19211671
1993 The surface cyclic AMP receptors, cAR1, cAR2, and cAR3, promote Ca2+ influx in Dictyostelium discoideum by a G alpha 2-independent mechanism. Molecular biology of the cell 58 8485319
2004 Ca2+ dependence of the Ca2+-selective TRPV6 channel. The Journal of biological chemistry 57 15184369
1992 Transcriptional repression of band 3 and CAII in v-erbA transformed erythroblasts accounts for an important part of the leukaemic phenotype. The EMBO journal 56 1354613
2012 Ca2+-dependent transcriptional control of Ca2+ homeostasis. The Journal of biological chemistry 55 22822058
2019 Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment. Cell communication and signaling : CCS 53 31847904
1996 Inhibition of Na+ and Ca2+ reabsorption by P2u purinoceptors requires PKC but not Ca2+ signaling. The American journal of physiology 53 8769822
1984 Variable CA II compartmentalization in vertebrate retina. Annals of the New York Academy of Sciences 51 6430181
2001 Overexpression of Na+/Ca2+ exchanger alters contractility and SR Ca2+ content in adult rat myocytes. American journal of physiology. Heart and circulatory physiology 50 11668069
2005 Modulation of Ca2+ signaling by Na+/Ca2+ exchangers in mast cells. Journal of immunology (Baltimore, Md. : 1950) 49 15611234
2005 Serine 68 of phospholemman is critical in modulation of contractility, [Ca2+]i transients, and Na+/Ca2+ exchange in adult rat cardiac myocytes. American journal of physiology. Heart and circulatory physiology 47 15653756
1999 Ca2+/calmodulin-dependent phosphorylation of the Ca2+-ATPase, uncoupled from phospholamban, stimulates Ca2+-pumping in native cardiac sarcoplasmic reticulum. Biochemical and biophysical research communications 47 10222236
2009 Measurement of nanomolar dissociation constants by titration calorimetry and thermal shift assay - radicicol binding to Hsp90 and ethoxzolamide binding to CAII. International journal of molecular sciences 46 19582223
1998 Thyroid control of sarcolemmal Na+/Ca2+ exchanger and SR Ca2+-ATPase in developing rat heart. The American journal of physiology 46 9688923
2004 Calcineurin inhibits Na+/Ca2+ exchange in phenylephrine-treated hypertrophic cardiomyocytes. The Journal of biological chemistry 44 15557343
1998 Ca2+ entry in CHO cells, after Ca2+ stores depletion, is mediated by arachidonic acid. Cell calcium 44 9883283
1990 Alterations in heart sarcolemmal Ca2(+)-ATPase and Ca2(+)-binding activities due to oxygen free radicals. Basic research in cardiology 44 2158297
2005 Ca2+ signalling in cardiogenesis. Cell calcium 43 16099501
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