Involvement of ryanodine receptors in IP3-mediated calcium signalling in neurons. A modelling approach

Phospholipase C (PLC)-coupled metabotropic receptors trigger the release of intracellular Ca2+ through activation of IP3 receptors (IP3Rs). Increasing evidence suggests that they can also and perhaps more efficiently mobilize Ca2+ through ryanodine receptors (RyRs). We constructed a model allowing a variable PLC stimulation level (via the parameter gamma) as well as a variable involvement of RyRs (via the parameter A). The sole presence of RyRs (A not = 0) affected the basal Ca2+ concentration [Ca2+]i. To keep Ca2+ below 160 nM, we fixed the upper limit of A to 0.2, a value that is compatible with the numerical ratio between RyRs and IP3Rs in cerebellar Purkinje neurons. Metabotropic responses were simulated by abruptly raising the value of gamma to various levels. In the absence of RyRs, the model starts to oscillate with gamma=0.4. For lower levels of PLC stimulation (gamma< or =0.3), the presence of RyR is capable of triggering an oscillatory signal. When A< or =0.18, the frequency of the Ca2+ oscillations augments from 0.1 to 1.3 Hz as a function of gamma. Conversely, as the frequency increases, the amplitude of the oscillations is reduced from 1 microM to 50 nM. With higher values of A, the oscillating pattern is definitively inhibited. It is concluded that RyRs have the potentiality to strikingly affect the temporal pattern of the Ca2+ signalling triggered by IP3-related metabotropic responses.