Abstract
Mutations in the sulfonylurea receptor 1 (SUR1), a subunit of ATP-sensitive potassium (K(ATP)) channels, cause familial hyperinsulinism. One such mutation, deletion of phenylalanine 1388 (DeltaPhe-1388), leads to defects in both trafficking and MgADP response of K(ATP) channels. Here we investigated the biochemical features of Phe-1388 that control the proper trafficking and function of K(ATP) 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 K(ATP) channels are generated.
Highlights
ATP-sensitive potassium (KATP) channels play a key role in linking metabolism to membrane excitability in muscle, neurons, and endocrine cells [1, 2]
Because the sulfonylurea receptor 1 (SUR1)-Phe-1388 equivalent position in SUR2A and SUR2B is occupied by a leucine, our results suggest that the conservative change between phenylalanine and leucine may serve as a mechanism for generating functional diversity in KATP channels
To examine which chemical features of the phenylalanine residue are critical for proper trafficking of the channel, we substituted Phe-1388 in SUR1 with all other 19 amino acids and determined how the substitutions affected surface expression of KATP channels
Summary
ATP-sensitive potassium (KATP) channels play a key role in linking metabolism to membrane excitability in muscle, neurons, and endocrine cells [1, 2]. Mutations in SUR1 or Kir6.2 attenuate or abolish KATP channel function by causing protein truncations or by affecting the ability of the channel to respond to MgADP [11, 21,22,23]. The mutant channels expressed on the cell surface showed no response to MgADP and would not be able to respond to metabolic changes.
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