Dysregulation of ryanodine receptors/Ca2+ release channels by FKBP12.6 in diabetic vascular myocytes

Abstract

Diabetes significantly increases mortality and morbidity from accompanying cerebral and other vascular diseases, which may result from an abnormally enhanced increase in [Ca2+]i in vascular smooth muscle cells (SMCs). However, the underlying molecular processes remain unclear. Here, we for the first time show that the activity of ryanodine receptors/Ca2+ release channels (RyRs) is greatly enhanced in diabetic cerebral artery SMCs (CASMCs). RyR‐mediated local Ca2+ release (Ca2+ spark) is significantly increased. Targeted gene knockout of FK506 binding protein 12.6 (FKBP12.6−/−), known to associate with and inhibit (stabilize) RyR2, increases Ca2+ spark as well. However, the increased Ca2+ spark is not further augmented in FKBP12.6−/−/diabetic cells. Caffeine, a classic RyR agonist, evokes an equivalent enhanced increase in [Ca2+]i (global Ca2+ release) in diabetic, FKBP12.6−/−, and FKBP12.6−/−/diabetic CASMCs. The amount of FKBP12.6 is largely decreased in SR fractions from diabetic cerebral arteries, and increased in cytosolic fractions, suggesting FKBP12.6/RyR dissociation. Supportively, FKBP12.6/RyR2 FRET signal is significantly decreased in diabetic CASMCs. Collectively, we conclude that FKBP12.6/RyR2 dissociation represents an essential mechanism in the diabetic increase in [Ca2+]i in vascular SMCs and associated vascular diseases.