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J Gen Physiol
2007 Aug 01;1302:217-21. doi: 10.1085/jgp.200709817.
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Cytoplasmic ATP inhibition of CLC-1 is enhanced by low pH.
Tseng PY
,
Bennetts B
,
Chen TY
.
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The CLC-1 Cl(-) channel is abundantly expressed on the plasma membrane of muscle cells, and the membrane potential of muscle cells is largely controlled by the activity of this Cl(-) channel. Previous studies showed that low intracellular pH increases the overall open probability of recombinant CLC-1 channels in various expression systems. Low intracellular pH, however, is known to inhibit the Cl(-) conductance on the native muscle membrane, contradicting the findings from the recombinant CLC-1 channels in expressed systems. Here we show that in the presence of physiological concentrations of ATP, reduction of the intracellular pH indeed inhibits the expressed CLC-1, mostly by decreasing the open probability of the common gate of the channel.
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17664348
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Figure 1. Effects of 1 mM cytoplasmic ATP on CLC-1 at three intracellular pH conditions. (A) Recording traces were obtained in the indicated pH and ATP conditions using voltage protocol A. (B) Normalized current (Inorm) represents the initial, tail current normalized to the maximal initial current in the absence of ATP. Each data point is the average from 3–6 patches. This Inorm value reflects the product of the fast-gate Po and the common-gate Po, namely Pof × Poc. Solid and open symbols were in 0 and 1 mM cytoplasmic ATP, respectively.
Figure 2. Effects of 1 mM ATP on the common gate of CLC-1. (A) Recording traces obtained in the indicated conditions using voltage protocol B. (B) Normalized value of the initial tail current (Inorm) in each pH condition (as shown in A). This Inorm value has been widely used to represent the Po of the common gate (Poc). Dividing the Inorm in Fig. 1 B (from protocol A) by the Inorm here (from protocol B) gives the fast-gate Po (Pof), which is shown in the inset of each panel. Solid and open symbols were obtained in 0 and 1 mM cytoplasmic ATP, respectively.
Figure 3. Dependence of the V1/2 of the common-gate Poc–V curve on the ATP concentration in three different pH conditions. Each data point is the average from 3–7 patches. Solid curves are drawn according to a Michaelis-Menten equation with the ATP half-effective concentration and the saturated V1/2 value of 0.31 mM and −20 mV (pH 7.4), 0.40 mM and +49 mV (pH 6.8), and 0.12 mM and +91 mV (pH 6.2).
Figure 4. Reversible ATP inhibition on the CLC-1 common-gate activity at pH 6.8. Top panels show recording traces by a pulse protocol of +40 mV test voltage (300 ms), followed by the short pulse to +170 mV (400 μs), and finally the tail voltage step at −120 mV. The recorded traces were shown around the initial tail current for those traces during ATP wash-in (left) and wash-out (right). Each recording trace is separated by 2 s, and the initial value of the tail current in each trace is plotted against time at the bottom panel. The red curve represents a single-exponential fit with a time constant of 3.4 s, which does not fit the ATP wash-in process well. Three other patches show the same results from such ATP wash-in and wash-out experiments.
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