Abstract:
:We searched for sites on the alpha-subunit of the fast Na(+) channel responsible for the difference in GTX (grayanotoxin) sensitivity of the skeletal- and cardiac-muscle Na(+) current. cDNA clones, encoding the skeletal or cardiac isoforms of the alpha-subunit, were inserted into a mammalian expression vector and transiently transfected into human embryonic kidney cells. The expressed channels were measured using whole-cell patch-clamp techniques and examined for GTX sensitivity. As a measure of GTX sensitivity, we used relative chord conductance (ratio of maximum chord conductance of noninactivating GTX-modified Na(+) currents to that of unmodified peak currents). Wild-type channels from skeletal muscle (mu 1) were more sensitive to GTX modification than wild-type cardiac channels (rH1) by a factor of 1.6. To facilitate exploration of alpha-subunit sites determining GTX sensitivity, we used SHHH, a chimera of skeletal muscle (S) domain D1 and heart muscle (H) domains D2D3D4 with supernormal sensitivity to GTX I (1.5-fold of wild-type mu 1). Successive replacement of Ser-251 (D1S4-S5 intracellular loop) and Ile-433 (D1S6 transmembrane segment), with corresponding rH1 residues Ala and Val, reduced, in a stepwise manner, the GTX sensitivity of the chimera and related mutants to that of wild-type rHl. We concluded that, in addition to Ile-433, known as the GTX-binding site, Ser-251 represents a novel site for GTX modification.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Kimura T,Yamaoka K,Kinoshita E,Maejima H,Yuki T,Yakehiro M,Seyama Ikeywords:
subject
Has Abstractpub_date
2001-10-01 00:00:00pages
865-72issue
4eissn
0026-895Xissn
1521-0111journal_volume
60pub_type
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