TY - JOUR
T1 - How to validate a heteromeric ion channel drug target
T2 - Assessing proper expression of concatenated subunits
AU - Sack, Jon T
AU - Shamotienko, Oleg
AU - Dolly, J. Oliver
PY - 2008/5
Y1 - 2008/5
N2 - Native subtypes of K+ and other ion channels are often hetero-oligomeric combinations of protein subunits. Drugs that selectively target relevant in vivo heteromers are valuable research tools and potential therapeutics. To recreate heteromeric channels as authentic drug targets, multiple subunits have been covalently tethered by concatemerizing their coding sequences. This perspective examines the linking strategies that have proven successful with many channel types and addresses some less desirable outcomes encountered. We discuss a variety of biochemical, electrophysiological, and pharmacological techniques that can assess whether constructs with concatenated subunits lead to expression of the intended uniform population of channels. Careful controls to ensure that channels are properly assembled can validate heterologously expressed concatemers as promising targets for the discovery of highly selective drugs.
AB - Native subtypes of K+ and other ion channels are often hetero-oligomeric combinations of protein subunits. Drugs that selectively target relevant in vivo heteromers are valuable research tools and potential therapeutics. To recreate heteromeric channels as authentic drug targets, multiple subunits have been covalently tethered by concatemerizing their coding sequences. This perspective examines the linking strategies that have proven successful with many channel types and addresses some less desirable outcomes encountered. We discuss a variety of biochemical, electrophysiological, and pharmacological techniques that can assess whether constructs with concatenated subunits lead to expression of the intended uniform population of channels. Careful controls to ensure that channels are properly assembled can validate heterologously expressed concatemers as promising targets for the discovery of highly selective drugs.
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U2 - 10.1085/jgp.200709939
DO - 10.1085/jgp.200709939
M3 - Article
C2 - 18411330
AN - SCOPUS:42949178643
VL - 131
SP - 415
EP - 420
JO - Journal of General Physiology
JF - Journal of General Physiology
SN - 0022-1295
IS - 5
ER -