Central Core Disease (CCD) and Malignant Hyperthermia (MH) are linked to single amino acid substitutions in the skeletal muscle Ca 2þ release channel, the type 1 ryanodine receptor (RyR1). We focus on two autosomal dominant (AD) 712a
effect of tetrapropylammonium (TPA) and Beryllium Fluoride (BeFx) on inward proton current (IH) transport by NKA expressed in Xenopus oocytes. TPA (a shared site blocker) had a dual effect on IH; between pH 7.6-6.0 TPA partially inhibited IH, and at pH 5.0 (where an inhibitory effect on the steady state IH is present), TPA partially activated IH. When the phosphate analogue BeFx was injected into oocytes, stabilizing an externally open conformation of the ion binding sites, K þ still inhibited inward current at pH 7.6. At pH 5.0 K þ activated IH resembling the effect of TPA on fully functional NKA. These results illustrate the complex interaction between the occupancy of shared sites and proton permeation. Blocking access at the shared sites with TPA activated IH by relieving the inhibition normally observed at high [H þ ]. Partial inhibition by TPA at pH 5.0 may reflect incomplete block of H þ access or a reduced rate of the conformational changes needed for H þ translocation. After BeFx inhibition NKA was still capable of interacting with K þ. The mixed occupancy of K þ and H þ at low pH activated the leak, likely relieving the H þ inhibition due to K þ occlusion.
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