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First published online May 15, 2009
Journal of Experimental Biology 212, 1672-1683 (2009)
Published by The Company of Biologists 2009
doi: 10.1242/jeb.029454

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Molecular physiology and genetics of Na⁺-independent SLC4 anion exchangers

Seth L. Alper

Renal Division and Molecular and Vascular Medicine Unit, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

View larger version (13K): [in this window] [in a new window]   Fig. 1. Schematic diagram of polypeptide variants expressed by the genes encoding the SLC4 Na+-independent anion exchangers, AE1, AE2 and AE3. Predicted transmembrane (TM) domains are blue. Total polypeptide lengths are on the right. Lengths of variant N-terminal sequences are indicated within the leftmost boxes, and lengths of variant C-terminal domains (for the AE3-14nt variants) in the rightmost boxes. Modified from Stewart et al. (Stewart et al., 2007).

View larger version (39K): [in this window] [in a new window]   Fig. 2. Proposed topographical model for the human SLC4A1/AE1 Cl–/HCO3– exchanger polypeptide, after Zhu et al. (Zhu et al., 2003). Met66 (arrow) marks the start of kidney AE1. Polymorphisms encoding blood group antigens are blue. The mutations associated with hereditary spherocytic anemia and ovalocytosis are orange, and include missense, nonsense, splicing and deletion mutations. Missense mutations associated with hereditary stomatocytosis and xerocytosis are red. Mutations associated with dominant and recessive distal renal tubular acidosis are green. Terminal deletions are in lighter orange and green. Upper left: scanning electron micrographs of wild-type erythrocytes and AE1–/– bovine spherocytes (HS) (Inaba et al., 1996). Upper right: consecutive semithin sections from rat kidney cortex immunostained with antibodies recognizing vH+-ATPase (left) and kAE1 (right). Only the Type A intercalated cell with apical vH+-ATPase expresses basolateral kAE1 (Alper et al., 1989). HS, hereditary spherocytic anemia; HSt, hereditary stomatocytosis; dRTA, distal renal tubular acidosis. Scale bars 10 µm at top left; 7 µm, top right. Modified from Shayakul and Alper, and Stewart (Shayakul and Alper, 2004; Stewart et al., 2007).

View larger version (47K): [in this window] [in a new window]   Fig. 3. Model of mouse AE2a NH2-terminal cytoplasmic domain amino acids 317–623, highlighting conserved residues required for normal regulation of Cl–/anion exchange by pHo and pHi. (A) Ribbon diagram structure of AE2 amino acids 317–623 based on the crystal structure of the corresponding region of human AE1 (Zhang et al., 2000). The structural model (B) and the linear schematic diagram (C) each indicate residues which when mutated alter AE2 regulation by pHi (yellow), by pHo (red) or by both pHi and pHo (orange). (B) Space-filling structure of AE2 amino acids 317–610, with surface amino acid residues indicated by the same colors. P610 (blue) is the most C-terminal surface residue in this view. Mutation en bloc of AE2 amino acids 403–408, at the bottom in pink, altered sensitivity only to pHo. AE2 amino acids 397–402 are located out of view at the bottom right, adjacent to amino acids 403–408. L323 is modeled to be not at the domain surface. (Modified from Stewart et al., 2004.)

View larger version (34K): [in this window] [in a new window]   Fig. 4. Re-entrant loop 1 (RL1) of the mouse AE2 transmembrane domain plays a critical role in the acute regulation of anion exchange by pH. Summary of transmembrane subdomains (shaded boxes) and individual amino acid residues identified from mutagenesis studies as contributing importantly to regulation of AE2 activity by pH, NH4+ and calmidazolium. Residues of RL1 interact with as yet unidentified amino acids within the TM1–6 region to mediate `pH sensor' functions in the AE2 transmembrane domain. Residues involved in regulation by pHo are gray, those involved in regulation by pHi are white, and those involved in regulation by both pHo and pHi are black. White boxes marked with an X are residues that when mutated yielded functional activity too low for study (modified from Stewart et al., 2008).

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