Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation.
BACKGROUND
Although defective Ca(2+) homeostasis may contribute to arrhythmogenesis in atrial fibrillation (AF), the underlying molecular mechanisms remain poorly understood. Studies in patients with AF revealed that impaired diastolic closure of sarcoplasmic reticulum (SR) Ca(2+)-release channels (ryanodine receptors, RyR2) is associated with reduced levels of the RyR2-inhibitory subunit FKBP12.6.


OBJECTIVE
The objective of the present study was to test the hypothesis that Ca(2+) leak from the SR through RyR2 increases the propensity for AF in FKBP12.6-deficient (-/-) mice.


METHODS
Surface electrocardiogram and intracardiac electrograms were recorded simultaneously in FKBP12.6-/- mice and wild-type (WT) littermates. Right atrial programmed stimulation was performed before and after injection of RyR2 antagonist tetracaine (0.5 mg/kg). Intracellular Ca(2+) transients were recorded in atrial myocytes from FKBP12.6-/- and WT mice.


RESULTS
FKBP12.6-/- mice had structurally normal atria and unaltered expression of key Ca(2+)-handling proteins. AF episodes were inducible in 81% of FKBP12.6-/-, but in only 7% of WT mice (P <.05), and were prevented by tetracaine in all FKBP12.6-/- mice. SR Ca(2+) leak in FKBP12.6-/- myocytes was 53% larger than in WT myocytes, and FKBP12.6-/- myocytes showed increased incidence of spontaneous SR Ca(2+) release events, which could be blocked by tetracaine.


CONCLUSIONS
The increased vulnerability to AF in FKBP12.6-/- mice substantiates the notion that defective SR Ca(2+) release caused by abnormal RyR2 and FKBP12.6 interactions may contribute to the initiation or maintenance of atrial fibrillation.
Sood
Subeena
S
Department of Molecular Physiology and Biophysics, Houston, Texas 77030, USA.
Chelu
Mihail G
MG
van Oort
Ralph J
RJ
Skapura
Darlene
D
Santonastasi
Marco
M
Dobrev
Dobromir
D
Wehrens
Xander H T
XH
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D004562:Electrocardiography; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D013748:Tetracaine / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002118:Calcium; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; D013748:Tetracaine; C509259:FKBP1B protein, mouse