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J. Gen. Physiol.,
Volume 113, Number 5, May 1, 1999 721-742
From the Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461
pH is a potent modulator of gap junction (GJ) mediated cell-cell communication. Mechanisms proposed for closure of GJ channels by acidification include direct actions of H+ on GJ proteins and indirect actions
mediated by soluble intermediates. Here we report on the effects of acidification on connexin (Cx)46 cell-cell
channels expressed in Neuro-2a cells and Cx46 hemichannels expressed in Xenopus oocytes. Effects of acidification on hemichannels were examined macroscopically and in excised patches that permitted rapid (<1 ms) and
uniform pH changes at the exposed hemichannel face. Both types of Cx46 channel were found to be sensitive to cytoplasmic pH, and two effects were evident. A rapid and reversible closure was reproducibly elicited with short
exposures to low pH, and a poorly reversible or irreversible loss occurred with longer exposures. We attribute the
former to pH gating and the latter to pH inactivation. Half-maximal reduction of open probability for pH gating
in hemichannels occurs at pH 6.4. Hemichannels remained sensitive to cytoplasmic pH when excised and when
cytoplasmic [Ca2+] was maintained near resting (~10
7 M) levels. Thus, Cx46 hemichannel pH gating does not
depend on cytoplasmic intermediates or a rise in [Ca2+]. Rapid application of low pH to the cytoplasmic face of
open hemichannels resulted in a minimum latency to closure near zero, indicating that Cx46 hemichannels directly sense pH. Application to closed hemichannels extended their closed time, suggesting that the pH sensor is
accessible from the cytoplasmic side of a closed hemichannel. Rapid closure with significantly reduced sensitivity
was observed with low pH application to the extracellular face, but could be explained by H+ permeation through
the pore to reach an internal site. Closure by pH is voltage dependent and has the same polarity with low pH applied to either side. These data suggest that the pH sensor is located directly on Cx46 near the pore entrance on
the cytoplasmic side.
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