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Paradoxical activation of an inwardly rectifying potassium channel mutant by spermine: "(b)locking" open the bundle crossing gate.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Vilin, Yury Y. Nunez, John-Jose Kim, Robin Y. Dake, Gregory R. Kurata, Harley T. |
| Copyright Year | 2013 |
| Abstract | Intracellular polyamines are endogenous blockers of inwardly rectifying potassium (Kir) channels and underlie steeply voltage-dependent rectification. Kir channels with strong polyamine sensitivity typically carry a negatively charged side chain at a conserved inner cavity position, although acidic residues at any pore-lining position in the inner cavity are sufficient to confer polyamine block. We have identified unique consequences of a glutamate substitution in the region of the helix bundle crossing of Kir6.2. Firstly, glutamate substitution at Kir6.2 residue F168 generates channels with intrinsic inward rectification that does not require blockade by intracellular polyamines or Mg(2+). In addition, these F168E channels exhibit a unique "spiked" tail phenotype, whereby large decaying inward tail currents are elicited upon spermine unbinding. This contrasts with the time-dependent recovery of current typically associated with blocker unbinding from ion channels. Interestingly, Kir6.2[F168E] channels exhibit a paradoxical biphasic conductance-voltage relationship in the presence of certain polyamines. This reflects channel blockade at positive voltages, channel stimulation at intermediate voltages, and exclusion of spermine from the pore at negative voltages. These features are recapitulated by a simple kinetic scheme in which weakly voltage-dependent spermine binding to a "shallow" site in the pore (presumably formed by the introduced glutamate at F168E) stabilizes opening of the bundle crossing gate. These findings illustrate the potential for dichotomous effects of a blocker in a long pore (with multiple binding sites), and offer a unique example of targeted modulation of the Kir channel gating apparatus. |
| Starting Page | 963 |
| Ending Page | 968 |
| Page Count | 6 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://molpharm.aspetjournals.org/content/molpharm/84/4/572.full.pdf |
| PubMed reference number | 23887925v1 |
| Alternate Webpage(s) | https://doi.org/10.1124/mol.113.086603 |
| DOI | 10.1124/mol.113.086603 |
| Journal | Molecular pharmacology |
| Volume Number | 84 |
| Issue Number | 4 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acids Binding Sites Body cavities Charge (electrical) Dental caries Exclusion Glutamic Acid Ion Channel Iontophoresis Killer-Cell Immunoglobulin-Like Receptor Kinetics Polyamines inward rectifier potassium channel spermine voltage |
| Content Type | Text |
| Resource Type | Article |
