In addition to the findings in ASM, previous studies by us and others revealed that RYR3 also localizes in perinuclear regions in vascular smooth muscle and chromaffin cells (ZhuGe et al., 2006; Clark et al., 2010). These findings suggested RYR3s could mediate specific unknown functions (Fig. 8 D). It is worth mentioning that in vascular smooth muscle cells without RYR3, the frequency and amplitude of STOCs are increased (Löhn et al., 2001). The authors suggest that under physiological conditions, these channels exert negative influence on RYR1/2, whose activation produces Ca2+ sparks. Furthermore, the authors proposed three possible mechanisms to account for this inhibition: (1) Ca2+ released from RYR3s inhibits either RYR1 or RYR2; (2) inactivation of VDCC that provides initial Ca2+ influx to trigger Ca2+ sparks; and (3) depletion of Ca2+ stores from which Ca2+ sparks occur. Given the distinctive distribution patterns of RYR1/2 and RYR3, it appears the first two mechanisms cannot account for the inhibition because a close proximity between RYR1/2 and RYR3 and between VDCC and RYR3 is required for these mechanisms to operate. If RYR1/2 and
