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Ph-Dependent Inhibition of Voltage-Gated H+ Currents in Rat Alveolar Epithelial Cells by Zn2+ and Other Divalent Cations
| Content Provider | Semantic Scholar |
|---|---|
| Author | Cherny, Vladimir DeCoursey, Thomas E. |
| Copyright Year | 1999 |
| Abstract | Inhibition by polyvalent cations is a defining characteristic of voltage-gated proton channels. The mechanism of this inhibition was studied in rat alveolar epithelial cells using tight-seal voltage clamp techniques. Metal concentrations were corrected for measured binding to buffers. Externally applied ZnCl(2) reduced the H(+) current, shifted the voltage-activation curve toward positive potentials, and slowed the turn-on of H(+) current upon depolarization more than could be accounted for by a simple voltage shift, with minimal effects on the closing rate. The effects of Zn(2+) were inconsistent with classical voltage-dependent block in which Zn(2+) binds within the membrane voltage field. Instead, Zn(2+) binds to superficial sites on the channel and modulates gating. The effects of extracellular Zn(2+) were strongly pH(o) dependent but were insensitive to pH(i), suggesting that protons and Zn(2+) compete for external sites on H(+) channels. The apparent potency of Zn(2+) in slowing activation was approximately 10x greater at pH(o) 7 than at pH(o) 6, and approximately 100x greater at pH(o) 6 than at pH(o) 5. The pH(o) dependence suggests that Zn(2+), not ZnOH(+), is the active species. Evidently, the Zn(2+) receptor is formed by multiple groups, protonation of any of which inhibits Zn(2+) binding. The external receptor bound H(+) and Zn(2+) with pK(a) 6.2-6.6 and pK(M) 6.5, as described by several models. Zn(2+) effects on the proton chord conductance-voltage (g(H)-V) relationship indicated higher affinities, pK(a) 7 and pK(M) 8. CdCl(2) had similar effects as ZnCl(2) and competed with H(+), but had lower affinity. Zn(2+) applied internally via the pipette solution or to inside-out patches had comparatively small effects, but at high concentrations reduced H(+) currents and slowed channel closing. Thus, external and internal zinc-binding sites are different. The external Zn(2+) receptor may be the same modulatory protonation site(s) at which pH(o) regulates H(+) channel gating. |
| Starting Page | 819 |
| Ending Page | 838 |
| Page Count | 20 |
| File Format | PDF HTM / HTML |
| DOI | 10.1085/jgp.114.6.819 |
| PubMed reference number | 10578017 |
| Journal | Medline |
| Volume Number | 114 |
| Alternate Webpage(s) | http://ftp.ncbi.nlm.nih.gov/pub/pmc/fa/09/GP-8094.PMC2230650.pdf |
| Alternate Webpage(s) | http://jgp.rupress.org/content/jgp/114/6/819.full.pdf |
| Alternate Webpage(s) | https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fa/09/GP-8094.PMC2230650.pdf |
| Alternate Webpage(s) | https://doi.org/10.1085/jgp.114.6.819 |
| Journal | The Journal of general physiology |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
