Publication: Serine-401 as a batrachotoxin- and local anesthetic-sensing residue in the human cardiac Na(+) channel
All || By Area || By Year| Title | Serine-401 as a batrachotoxin- and local anesthetic-sensing residue in the human cardiac Na(+) channel | Authors/Editors* | Wang SY, Tikhonov DB, Zhorov BS, Mitchell J, Wang GK |
|---|---|
| Where published* | Pflugers Arch. |
| How published* | Journal |
| Year* | 2007 |
| Volume | 454 |
| Number | 2 |
| Pages | 277-287 |
| Publisher | |
| Keywords | |
| Link | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17205354&query_hl=1&itool=pubmed_docsum |
| Abstract |
Sequence alignment of four S6 segments in the human cardiac Na(+) channel suggests that serine-401 (hNav1.5-S401) at D1S6 along with asparagine-927 (N927) at D2S6, serine-1458 (S1458) at D3S6, and phenylalanine-1760 (F1760) at D4S6 may jointly form a pore-facing S(401)N(927)S(1458)F(1760) ring. Importantly, this pore-facing structure is adjacent to the putative gating-hinge (G(400)G(926)G(1457)S(1759)) and close to the selectivity filter. Within this SNSF ring, only S401 has not yet been identified as a batrachotoxin (BTX) sensing residue. We therefore created S401 mutants with 12 substitutions (S401C,W,P,A,K,F,R,E,L,N,D,G) and assayed their BTX sensitivity. All S401 mutants expressed Na(+) currents but often with altered gating characteristics. Ten mutants were found sensitive to 5 muM BTX, which eliminated Na(+) channel fast inactivation after repetitive pulses. However, S401K and S401R became BTX resistant. In addition, the block of open and inactivated hNav1.5-S401K Na(+) channels by local anesthetic bupivacaine was reduced by approximately 8-10-fold, but not the block of resting Na(+) channels. Qualitatively, these ligand-sensing phenotypes of hNav1.5-S401K channels resemble those of S1458K and F1760K channels reported earlier. Together, our results support that residue hNav1.5-S401 at D1S6 is facing the inner cavity and is in close proximity to the receptor sites for BTX and for local anesthetics. |
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