Microdomains formed by FKBP12.6 with RyR2 and BK channels in regulation of vascular tone

Ryanodine receptors (RyRs)/calcium release channels and big‐conductance calcium‐activated potassium (BK) channels are both important for numerous physiological responses, including vascular tone. We provide biochemical evidence showing that FK506 binding protein 12.6 (FKBP12.6) is physically associated to RyR2 in vascular smooth muscle cells (VSMCs). Chemical removal of FKBP12.6 significantly increases the activity of RyRs and intracellular Ca 2+ release. Genetic removal of FKBP12.6 produces similar stimulatory effects. Interestingly, FKBP12.6 is also specifically bound to BK channels in VSMCs. Inside‐out single channels recordings show that application of FK506 to remove FKBP12.6 significantly decreases the open probability of BK channels. The effect of FK506 is concentration‐dependent. Similar to chemical removal of FKBP12.6 with FK506 exposure, genetic removal of FKBP12.6 with gene deletion produces an inhibitory effect on the activity of single BK channels as well. FKBP12.6 gene deletion can reduce the sensitivity of BK channels to voltage and calcium. Moreover, FKBP2.6 gene deletion augments agonist‐evoked vascular constriction. Moreover, blood pressure is higher in FKBP12.6 gene deletion mice than control mice. In conclusion, our findings for the first time demonstrate that FKBP12.6 is associated with BK channels and RyR2 to form cellular microdomains in CASMCs, which play an important role in controlling vascular tone and blood pressure.