Premium
FK506 binding protein (FKBP12) may contribute to 4‐chloro‐m‐cresol induced adenosine in human B cells
Author(s) -
Bina Saiid,
Capacchione John,
Bayarsaikhan Munkhuu,
Muldoon Sheila,
Bunger Rolf
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1002.27
Subject(s) - ryanodine receptor , ehna , chemistry , fkbp , agonist , intracellular , cytosol , receptor , adenosine , adenosine deaminase , microbiology and biotechnology , pharmacology , medicine , biochemistry , biology , enzyme
Ryanodine receptor (RyR1) agonist 4‐chloro‐m‐cresol (4CmC) stimulates normoxic adenosine (ADO) production in B cells, especially from malignant hyperthermia susceptible individuals. In an attempt to identify a pathway for this action of 4CmC, FK506, an immunosuppressant drug that disrupts the interaction of FK506‐binding protein (FKBP12) with RyR1, and Xestospongin C (XeC), a specific inhibitor of IP3R were tested. FKBP12 forms a complex with the RyR and IP3R to regulate their physiological release of intracellular Ca2+. Methods B cells were suspended in HBSS + ADO deaminase inhibitor (EHNA) followed by addition of FK506 or XeC and incubated at 37°C for 10 min. In a 2nd experiment; 10min after addition of FK506 or XeC, 4CmC (2mM) was applied and incubation continued for 30 min. After cellular reactions termination, supernatant [ADO] was assayed using HPLC. Results (means ± SEM for 106 cells): ADO basal level was 0.422 ± 0.097μM (n=7). FK506 (2, 20, 200μM) increased ADO levels by 59 ± 4, 207 ± 21, and 240 ± 24% respectively. FK506 (2, 20, 200μM) increased the sensitivity of B cells to 4CmC by 4±5, 13±4, and 49±10%. XeC did not alter basal or 4CmC‐induced ADO in B cells. Conclusion FK506 likely displaces FKBP12 from the RyR1 receptor in B cells resulting in leaky Ca2+ channels and to cytosolic Ca2+ accumulation. This stimulates Ca2+ pumping, generating ADP and AMP leading to formation of ADO in the presence of EHNA.