Nitric oxide-induced calcium release via ryanodine receptors regulates neuronal function

Abstract

Mobilization of intracellular Ca 2 þ stores regulates a multitude of cellular functions, but the role of intracellular Ca 2 þ release via the ryanodine receptor (RyR) in the brain remains incompletely understood. We found that nitric oxide (NO) directly activates RyRs, which induce Ca 2 þ release from intracellular stores of central neurons, and thereby promote prolonged Ca 2 þ signalling in the brain. Reversible S-nitrosylation of type 1 RyR (RyR1) triggers this Ca 2 þ release. NO-induced Ca 2 þ release (NICR) is evoked by type 1 NO synthase-dependent NO production during neural firing, and is essential for cerebellar synaptic plasticity. NO production has also been implicated in pathological conditions including ischaemic brain injury, and our results suggest that NICR is involved in NO-induced neuronal cell death. These findings suggest that NICR via RyR1 plays a regulatory role in the physiological and pathophysiological functions of the brain.

Nitric oxide-induced calcium release

“…In conclusion, in combination with the observations in our previous study, 15 it is suggested that NICR is dependent on the NO-dependent S-nitrosylation of RyR1 rather than on indirect actions of peroxynitrite or cyclic GMP (Fig. 3).…”

“…However, it was resistant to an intracellular application of 10 mM ascorbic acid, which completely abolishes BS-induced NICR. 15 Therefore, the peroxynitrite-dependent digitized at 20 kHz. After obtaining a stable initial recording for at least 10 min, 60 burst stimulations (1 burst stimulation: 5 pulses at 50 Hz) were repeatedly applied at 1 Hz to induce LTP.…”

“…23,24 We S-nitrosylation of RyR1 at cysteine 3635 is both necessary and sufficient for the NO-induced Ca 2+ increase, which is hereafter referred to as "NO-induced Ca 2+ release (NICR)." 15 We then showed that BS to PFs induces intracellular Ca 2+ release in PC dendrites. When BSwhich induces NO-dependent-LTP-was applied to PF, Ca 2+ levels were transiently but clearly elevated in PC dendrites.…”

Roles of ryanodine receptors in the central nervous system

“…Ayrica RyR soma ve dendritlerde, aksonlarda, pre-ve post-sinaptik terminallerde yer almaktadir [8,9]. Purkinje hücrelerinin dendritlerinde de çok miktarda RyR1 eksprese edilir [12].…”

Loss of endoplasmic reticulum Ca2+ homeostasis: contribution to neuronal cell death during cerebral ischemia

“…Moreover, maximal activation can be attained at lower concentrations of ATP for oxidized RyR channels [21] . Alternatively, Kakizawa [22] recently showed that nitric oxide (NO) can induce RyR1 activation through S-nitrosylation at a specific cysteine residue (C3635) and evoke Ca 2+ release from the ER. Using cultured neurons derived from RyR1 -/-mice, in which NO-induced Ca 2+ release is absent, they demonstrated that NO-induced neuronal cell death was reduced.…”