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Importance of uncharged polar residues and proline in the proximal two-thirds (Pro107-Ser128) of the highly conserved region of mouse ileal Na+-dependent bile acid transporter, Slc10a2, in transport activity and cellular expression.
- Source :
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BMC physiology [BMC Physiol] 2013 Feb 04; Vol. 13, pp. 4. Date of Electronic Publication: 2013 Feb 04. - Publication Year :
- 2013
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Abstract
- Background: SLC10A2-mediated reabsorption of bile acids at the distal end of the ileum is the first step in enterohepatic circulation. Because bile acids act not only as detergents but also as signaling molecules in lipid metabolism and energy production, SLC10A2 is important as the key transporter for understanding the in vivo kinetics of bile acids. SLC10A family members and the homologous genes of various species share a highly conserved region corresponding to Gly104-Pro142 of SLC10A2. The functional importance of this region has not been fully elucidated.<br />Results: To elucidate the functional importance of this region, we previously performed mutational analysis of the uncharged polar residues and proline in the distal one-third (Thr130-Pro142) of the highly conserved region in mouse Slc10a2. In this study, proline and uncharged polar residues in the remaining two-thirds of this region in mouse Slc10a2 were subjected to mutational analysis, and taurocholic acid uptake and cell surface localization were examined. Cell surface localization of Slc10a2 is necessary for bile acid absorption. Mutants in which Asp or Leu were substituted for Pro107 (P107N or P107L) were abundantly expressed, but their cell surface localization was impaired. The S126A mutant was completely impaired in cellular expression. The T110A and S128A mutants exhibited remarkably enhanced membrane expression. The S112A mutant was properly expressed at the cell surface but transport activity was completely lost. Replacement of Tyr117 with various amino acids resulted in reduced transport activity. The degree of reduction roughly depended on the van der Waals volume of the side chains.<br />Conclusions: The functional importance of proline and uncharged polar residues in the highly conserved region of mouse Slc10a2 was determined. This information will contribute to the design of bile acid-conjugated prodrugs for efficient drug delivery or SLC10A2 inhibitors for hypercholesterolemia treatment.
- Subjects :
- Animals
Bile Acids and Salts genetics
Bile Acids and Salts metabolism
Biological Transport
DNA Mutational Analysis methods
Ileum cytology
Kinetics
Mice
Mutation
Organic Anion Transporters, Sodium-Dependent genetics
Proline genetics
Structure-Activity Relationship
Symporters genetics
Taurocholic Acid genetics
Taurocholic Acid metabolism
Conserved Sequence
Ileum metabolism
Organic Anion Transporters, Sodium-Dependent chemistry
Organic Anion Transporters, Sodium-Dependent metabolism
Proline chemistry
Proline metabolism
Symporters chemistry
Symporters metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1472-6793
- Volume :
- 13
- Database :
- MEDLINE
- Journal :
- BMC physiology
- Publication Type :
- Academic Journal
- Accession number :
- 23374508
- Full Text :
- https://doi.org/10.1186/1472-6793-13-4