招博士后

Outstanding opportunities are currently available for two individuals

to participate in a   high-quality, team-oriented research environment. An ope

ning is available immediately (spring, 2003) for one postdoctoral level scient

ist to work on projects utilizing electrophysiological methods to study questi

ons relating to ion channel structure and function. In addition, we are intere

sted in a second postdoctoral level scientist with primary expertise in molecu

lar biology and protein chemistry.  



Examples of research projects for which a highly motivated, independent, energ

etic person is needed include the following.



1. Structure-function studies on BK-type Ca2+ and voltage-dependent K+ channel

s



Ca2+-mediated gating of BK channels appears to involve multiple regulatory ele

ments, involving perhaps two high affinity binding sites and a low affinity no

n-selective divalent cation binding site (Zhang et al., 2001; Xia et al., 2002

). We are investigating the role of different portions of the BK channel in me

diating the effects of Ca2+ (Lingle, 2002).



2. Structure and functional consequences of BK b subunits.


   To date, four members of a BK channel b subunit accessory subunit family ha

ve been identified. b subunits play a profound role in defining the phenotypic
 properties of BK channels in native cells, including the Ca2+-dependence of g

ating and inactivation behavior (Xia et al., 1999; Xia et al., 2000). As yet,

the tissue specific localization of different family members and the functiona

l role of the different b subunits remains to be fully defined. We are current

ly examining the functional properties of different b subunits and attempting

to define the regions of these subunits that are responsible for their unique

functional properties (Wang et al., 2002; Lingle et al., 2001; Zeng et al., 20

01). In particular, our results suggest that the extracellular segments of the
 four b subunits that can contribute to a complete channel may form a tetramer

ic structure that overlays the extracellular end of the BK channel.  This stru

cture can influence not only sensitivity of BK channels to scorpion

toxins, but access of permeant ions to the channel.  



3. Structural basis of BK channel inactivation


  We continue to examine the mechanistic and structural bases for the similari

ties and differences between inactivation mediated by inactivation domains of

Kv channels and of b subunits of BK channels (Lingle et al., 2001; Xia et al.,
 2003).  Our working hypothesis is that, in both cases, inactivation results f

rom linear insertion of an N-terminal peptide segment into the ion permeation

pathway, thereby obstructing ion permeation. Because of differences in perhaps
 the length, diameter, or contour of the ion permeation pathway, the average p

osition occupied by the N-terminal peptide may differ between KV and BK channe

ls, thereby resulting in functional differences in some of the phenomenology o

f inactivation.  



Interested individuals should forward a CV and letters of recommendation to





Chris Lingle

Washington Univ. Sch. Med.

Dept. Anesthesiology

Box 8054

St. Louis, MO 63110
 



Or, by email, clingle@morpheus.wustl.edu