Untangling the inseparable life of an ABC transporter and a potassium channel: Towards understanding the structure-function relationship in the KATP channel complex.

Abstract

KATP channels are unique protein complexes of a potassium channel, Kir6.1 or Kir6.2, and an ABC transporter, SUR1, SUR2A or SUR2B (splice variants of SUR2), in a 4:4 stoichiometry. Broadly expressed in many cell types and tissues, KATP channels couple changes in cellular metabolic activity with membrane excitability to control a wide range of physiological processes, including hormone secretion, control of vascular tone, learning and memory, and cardiac and neuronal protection against ischemic insults. In pancreatic β-cells KATP channels formed by Kir6.2 and SUR1 control insulin secretion, and gain- or loss-of-function mutations in these channels cause neonatal diabetes or congenital hyperinsulinism, respectively. Physiological activity of pancreatic KATP channels is regulated by intracellular ATP and ADP. Non-hydrolytic binding of ATP to Kir6.2 inhibits channel activity, while MgATP and MgADP binding to the nucleotide binding domains (NBDs) of SUR1 stimulates channel activity. Besides ATP and ADP, membrane phospholipids in particular PIP2 interacts with Kir6.2 and stimulates channel activity. In addition, pharmacological inhibitors and activators act on SUR1 to modulate channel activity. Although Kir6.2 and SUR1 harbor the primary binding sites for specific physiological and pharmacological ligands, both subunits participate in ligand regulation. How do the potassium channel and the silent ABC transporter work together to decipher signals from different ligands for gating has long been a major question in the KATP channel field. Here, I present structural and functional evidence that SUR1 contributes directly to ATP and PIP2 binding via its TMD0 and L0 linker to enhance Kir6.2 sensitivity to both ligands. Moreover, SUR1 regulates Kir6.2 activity allosterically via its dynamic interaction with the N-terminus of Kir6.2.