Differential regulation of calcineurin isoforms in transplant patients: a new look at an old problem. Transplantation 2013 Aug 15;96(3):239-44
Date
07/05/2013Pubmed ID
23823650DOI
10.1097/TP.0b013e31829acb64Scopus ID
2-s2.0-84881611142 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
BACKGROUND: Calcineurin is a ubiquitously expressed calcium-dependent phosphatase that is inhibited by the immunosuppressant drugs cyclosporine and tacrolimus. Measuring calcineurin activity in transplant patients has been complicated by a lack of consistent correlation between drug level and enzyme activity, particularly with chronic use. Data from mice lacking the CnAα or CnAβ isoform of the catalytic subunit of calcineurin demonstrate that loss of CnAβ results in immunosuppression, whereas loss of CnAα does not. As such, methods to examine activity of the CnAβ isoform may be more clinically relevant than nonspecific assays.
METHODS: Because the current enzyme assays are nonisoform specific, we examined association of the CnAα or CnAβ isoform with calmodulin (CaM), a shared binding protein that is only associated with the catalytic subunit in the presence of calcium. We then compared semiquantitated data with total calcineurin activity and immune status in a cohort of pretransplantation controls and postrenal transplantation patients.
RESULTS: We found no difference in calcineurin activity between the groups and no difference in the amount of non-isoform-specific catalytic subunit bound to CaM. However, association of CnAα-CaM is increased in transplant patients, whereas CnAβ-CaM is decreased. In addition, the amount of CnAβ-CaM corresponds positively with T-cell activity and negatively with tacrolimus level. Finally, CnAβ-CaM is lower in stable transplant patients compared with those with acute rejection.
CONCLUSIONS: These data suggest that monitoring specifically the β isoform may be more informative than non-isoform-specific assay methods.
Author List
Pena JA, Titus L, Jackson J, Kirk AD, Gooch JLAuthor
Lauren Titus MD Assistant Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCalcineurin
Calcineurin Inhibitors
Female
Humans
Immunosuppressive Agents
Kidney Transplantation
Male
Mice
Middle Aged
Protein Isoforms