Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasmalemmal Cl(-)/HCO(3)(-) exchangers are encoded by the SLC4 and SLC26 gene superfamilies, and function to regulate intracellular pH, [Cl(-)] and cell volume. The Cl(-)/HCO(3)(-) exchangers of polarized epithelial cells also contribute to transepithelial secretion and reabsorption of acid-base equivalents and Cl(-). This review focuses on Na(+)-independent electroneutral Cl(-)/HCO(3)(-) exchangers of the SLC4 family. Human SLC4A1/AE1 mutations cause the familial erythroid disorders of spherocytic anemia, stomatocytic anemia and ovalocytosis. A largely discrete set of AE1 mutations causes familial distal renal tubular acidosis. The Slc4a2/Ae2(-/-) mouse dies before weaning with achlorhydria and osteopetrosis. A hypomorphic Ae2(-/-) mouse survives to exhibit male infertility with defective spermatogenesis and a syndrome resembling primary biliary cirrhosis. A human SLC4A3/AE3 polymorphism is associated with seizure disorder, and the Ae3(-/-) mouse has increased seizure susceptibility. The transport mechanism of mammalian SLC4/AE polypeptides is that of electroneutral Cl(-)/anion exchange, but trout erythroid Ae1 also mediates Cl(-) conductance. Erythroid Ae1 may mediate the DIDS-sensitive Cl(-) conductance of mammalian erythrocytes, and, with a single missense mutation, can mediate electrogenic SO(4)(2-)/Cl(-) exchange. AE1 trafficking in polarized cells is regulated by phosphorylation and by interaction with other proteins. AE2 exhibits isoform-specific patterns of acute inhibition by acidic intracellular pH and independently by acidic extracellular pH. In contrast, AE2 is activated by hypertonicity and, in a pH-independent manner, by ammonium and by hypertonicity. A growing body of structure-function and interaction data, together with emerging information about physiological function and structure, is advancing our understanding of SLC4 anion exchangers.
 ...
PMID:Molecular physiology and genetics of Na+-independent SLC4 anion exchangers. 1944 77

Anion exchanger 3 (AE3), expressed in the brain, heart, and retina, extrudes intracellular HCO(3)(-) in exchange for extracellular Cl(-). The SLC4A3 gene encodes two variants of AE3, brain or full-length AE3 (AE3(fl)) and cardiac AE3 (cAE3). Epilepsy is a heterogeneous group of disorders characterized by recurrent unprovoked seizures that affect about 50 million people worldwide. The AE3-A867D allele in humans has been associated with the development of IGE (IGE), which accounts for approximately 30% of all epilepsies. To examine the molecular basis for the association of the A867D allele with IGE, we characterized wild-type (WT) and AE3(fl)-A867D in transfected human embryonic kidney (HEK)-293 cells. AE3(fl)-A867D had significantly reduced transport activity relative to WT (54 +/- 4%, P < 0.01). Differences in expression levels or the degree of protein trafficking to the plasma membrane did not account for the defect of AE3(fl)-A867D. Treatment with 8-bromo-cAMP (8-Br-cAMP) increased Cl(-)/HCO(3)(-) exchange activity of WT and AE3(fl)-A867D to a similar degree, which was abolished by preincubation with the protein kinase A (PKA)-specific inhibitor H89. This indicates that PKA regulates WT and AE3(fl)-A867D Cl(-)/HCO(3)(-) exchange activity. No difference in Cl(-)/HCO(3)(-) exchange activity was found between cultures of mixed populations of neonatal hippocampal cells from WT and slc4a3(-/-) mice. We conclude that the A867D allele is a functional (catalytic) mutant of AE3 and that the decreased activity of AE3(fl)-A867D may cause changes in cell volume and abnormal intracellular pH. In the brain, these alterations may promote neuron hyperexcitability and the generation of seizures.
 ...
PMID:Characterization of an epilepsy-associated variant of the human Cl-/HCO3(-) exchanger AE3. 1960 33