{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T22:48:33Z","timestamp":1778885313339,"version":"3.51.4"},"reference-count":71,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,11,1]]},"abstract":"<jats:p>The activation gate of ion channels controls the transmembrane flux of permeant ions. In voltage-gated K+ channels, the aperture formed by the S6 bundle crossing can widen to open or narrow to close the ion permeation pathway, whereas the selectivity filter gates ion flux in cyclic-nucleotide gated (CNG) and Slo1 channels. Here we explore the structural basis of the activation gate for Slo2.1, a weakly voltage-dependent K+ channel that is activated by intracellular Na+ and Cl\u2212. Slo2.1 channels were heterologously expressed in Xenopus laevis oocytes and activated by elevated [NaCl]i or extracellular application of niflumic acid. In contrast to other voltage-gated channels, Slo2.1 was blocked by verapamil in an activation-independent manner, implying that the S6 bundle crossing does not gate the access of verapamil to its central cavity binding site. The structural basis of Slo2.1 activation was probed by Ala scanning mutagenesis of the S6 segment and by mutation of selected residues in the pore helix and S5 segment. Mutation to Ala of three S6 residues caused reduced trafficking of channels to the cell surface and partial (K256A, I263A, Q273A) or complete loss (E275A) of channel function. P271A Slo2.1 channels trafficked normally, but were nonfunctional. Further mutagenesis and intragenic rescue by second site mutations suggest that Pro271 and Glu275 maintain the inner pore in an open configuration by preventing formation of a tight S6 bundle crossing. Mutation of several residues in S6 and S5 predicted by homology modeling to contact residues in the pore helix induced a gain of channel function. Substitution of the pore helix residue Phe240 with polar residues induced constitutive channel activation. Together these findings suggest that (1) the selectivity filter and not the bundle crossing gates ion permeation and (2) dynamic coupling between the pore helix and the S5 and S6 segments mediates Slo2.1 channel activation.<\/jats:p>","DOI":"10.1085\/jgp.201311064","type":"journal-article","created":{"date-parts":[[2013,10,28]],"date-time":"2013-10-28T15:53:17Z","timestamp":1382975597000},"page":"523-542","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Structural basis of ion permeation gating in Slo2.1 K+ channels"],"prefix":"10.1085","volume":"142","author":[{"given":"Priyanka","family":"Garg","sequence":"first","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute 1 , 2 , and 3"},{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry 1 , 2 , and 3"},{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112 1 , 2 , and 3"},{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute 1 , 2 , and 3"},{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry 1 , 2 , and 3"},{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112 1 , 2 , and 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Gardner","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute 1 , 2 , and 3"},{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry 1 , 2 , and 3"},{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112 1 , 2 , and 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivek","family":"Garg","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute 1 , 2 , and 3"},{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry 1 , 2 , and 3"},{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112 1 , 2 , and 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Sanguinetti","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute 1 , 2 , and 3"},{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry 1 , 2 , and 3"},{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112 1 , 2 , and 3"},{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute 1 , 2 , and 3"},{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry 1 , 2 , and 3"},{"name":"Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112 1 , 2 , and 3"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2013,10,28]]},"reference":[{"key":"2023072623052440200_bib1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/0896-6273(92)90160-F","article-title":"Calcium-activated potassium channels expressed from cloned complementary DNAs","volume":"9","author":"Adelman","year":"1992","journal-title":"Neuron."},{"key":"2023072623052440200_bib2","doi-asserted-by":"publisher","first-page":"re10","DOI":"10.1126\/stke.2003.188.re10","article-title":"Voltage-gated K channels","volume":"2003","author":"Armstrong","year":"2003","journal-title":"Sci. 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