Science Topics - 63

Ca²⁺-induced Ca²⁺ release (CICR) via ryanodine receptors (RyRs) in the somata of bullfrog sympathetic neurons plays a very important role in regulating membrane excitability (Akita & Kuba, J Gen Physiol 116:697-720, 2000). In our recent study, we found that this CICR is tightly regulated by a Ca²⁺-dependent “inactivation” mechanism (Akita & Kuba, J Physiol 586:3365-84, 2008). The observable [Ca²⁺]_i rise evoked by Ca²⁺ entry at the beginning of membrane depolarization was solely due to CICR in this neuron, and this CICR was inactivated within 10-20 ms when the Ca²⁺ entry continued. The inactivation was inhibited by intracellular BAPTA (IC₅₀»0.4 mM) but not by EGTA (≦10 mM), indicating that it must be mediated by some Ca²⁺-sensing molecules located close to (at ~60 nm from) voltage-gated Ca²⁺ channels and/or RyRs, and that the molecules must be exposed to a high [Ca²⁺]_i at the edges of “Ca²⁺ microdomains” during Ca²⁺ entry. Moreover, the longer duration of Ca²⁺ entry persisting after CICR inactivation was found to cause slower [Ca²⁺]_i decay after the end of Ca²⁺ entry. This was inhibited in parallel with the inhibition of inactivation by BAPTA. Thus, some mechanism counteracting Ca²⁺ clearance must be linked to the inactivation mechanism, and this should provide the basis for the prolonged suppression of membrane excitability through activation of Ca²⁺-sensitive K⁺ channels after a longer period of membrane depolarization.

 

Supplementary information for figure: The Ca²⁺ sensor for inactivation is highly likely to reside in the molecules different from RyRs, although they are yet to be identified. The mechanism counteracting [Ca²⁺]_i decay would presumably be the weak Ca²⁺ release from RyRs in the “flickeringly” open mode, which must be converted from the inactivated state.

 

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*Laboratory of Correlative Physiology, National Institute for Physiological Sciences