TY - JOUR
T1 - Modulation of the trafficking efficiency and functional properties of ATP-sensitive potassium channels through a single amino acid in the sulfonylurea receptor
AU - Cartier, Etienne A.
AU - Shu, Shen
AU - Shyng, Show Ling
PY - 2003/2/28
Y1 - 2003/2/28
N2 - Mutations in the sulfonylurea receptor 1 (SUR1), a subunit of ATP-sensitive potassium (KATP) channels, cause familial hyperinsulinism. One such mutation, deletion of phenylalanine 1388 (ΔPhe-1388), leads to defects in both trafficking and MgADP response of KATP channels. Here we investigated the biochemical features of Phe-1388 that control the proper trafficking and function of KATP channels by substituting the residue with all other 19 amino acids. Whereas surface expression is largely dependent on hydrophobicity, channel response to MgADP is governed by multiple factors and involves the detailed architecture of the amino acid side chain. Thus, structural features in SUR1 required for proper channel function are distinct from those required for correct protein trafficking. Remarkably, replacing Phe-1388 by leucine profoundly alters the physiological and pharmacological properties of the channel. The F1388L-SUR1 channel has increased sensitivity to MgADP and metabolic inhibition, decreased sensitivity to glibenclamide, and responds to both diazoxide and pinacidil. Because this conservative amino acid substitution occurs in the SUR2A and SUR2B isoforms, the mutation provides a mechanism by which functional diversities in KATP channels are generated.
AB - Mutations in the sulfonylurea receptor 1 (SUR1), a subunit of ATP-sensitive potassium (KATP) channels, cause familial hyperinsulinism. One such mutation, deletion of phenylalanine 1388 (ΔPhe-1388), leads to defects in both trafficking and MgADP response of KATP channels. Here we investigated the biochemical features of Phe-1388 that control the proper trafficking and function of KATP channels by substituting the residue with all other 19 amino acids. Whereas surface expression is largely dependent on hydrophobicity, channel response to MgADP is governed by multiple factors and involves the detailed architecture of the amino acid side chain. Thus, structural features in SUR1 required for proper channel function are distinct from those required for correct protein trafficking. Remarkably, replacing Phe-1388 by leucine profoundly alters the physiological and pharmacological properties of the channel. The F1388L-SUR1 channel has increased sensitivity to MgADP and metabolic inhibition, decreased sensitivity to glibenclamide, and responds to both diazoxide and pinacidil. Because this conservative amino acid substitution occurs in the SUR2A and SUR2B isoforms, the mutation provides a mechanism by which functional diversities in KATP channels are generated.
UR - http://www.scopus.com/inward/record.url?scp=0037470177&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037470177&partnerID=8YFLogxK
U2 - 10.1074/jbc.M211395200
DO - 10.1074/jbc.M211395200
M3 - Article
C2 - 12496311
AN - SCOPUS:0037470177
SN - 0021-9258
VL - 278
SP - 7081
EP - 7090
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 9
ER -