“…Thus, channels or transporters aside from the ClC could be important conduits for P i into the SR. As P i -activation of the RyR did not prevent P i -mediated inhibition of spark frequency or declines in free [Ca 2+ ] SR at high [P i ], the putative activation of RyR by ClC blockers other than 9AC should not preclude the notion that these ClC blockers could mitigate the P i -mediated inhibition of spark frequency or declines in [Ca 2+ ] SR when [P i ] is high. As different ClC blockers could vary in effectiveness against different types of transporters and anion channels, an exploration of this variability could help determine the specific access point(s) for P i into the SR. Ferreira et al (2021) have provided compelling evidence that Ca 2+ and P i precipitate in the SR and that the passage of P i into the SR is mitigated by the ClC blocker 9AC. However, since 9AC is not specific to the ClC, P i could conceivably enter the SR via another 9AC-sensitive pathway.…”