Inwardly rectifying K+ (Kir) channels allow K+ to move more easily into rather than out of the cell. They have diverse physiological functions depending on their type and their location. There are ...

Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles

The Kir3.1 K(+) channel participates in heart rate control and neuronal excitability through G-protein and lipid signaling pathways. Expression in Escherichia coli has been achieved by replacing three fourths of the transmembrane pore with the pore of a prokaryotic Kir channel, leaving the cytoplasmic pore and membrane interfacial regions of Kir3.1 origin. Two structures were determined at 2.2 A. The selectivity filter is identical to the Streptomyces lividans K(+) channel within error of measurement (r.m.s.d.<0.2 A), suggesting that K(+) selectivity requires extreme conservation of three-dimensional structure. Multiple K(+) ions reside within the pore and help to explain voltage-dependent Mg(2+) and polyamine blockade and strong rectification. Two constrictions, at the inner helix bundle and at the apex of the cytoplasmic pore, may function as gates: in one structure the apex is open and in the other, it is closed. Gating of the apex is mediated by rigid-body movements of the cytoplasmic pore subunits. Phosphatidylinositol 4,5-biphosphate-interacting residues suggest a possible mechanism by which the signaling lipid regulates the cytoplasmic pore.

/pdf/crystal-structure-of-a-kir3-1-prokaryotic-kir-channel-2uyf6ifyoo.pdf

Crystal structure of a Kir3.1-prokaryotic Kir channel chimera.

Changes in intracellular pH regulate many cell behaviors, including proliferation, migration, and transformation. However, our understanding of how physiological changes in pH affect protein conformations and macromolecular assemblies is limited. We present design principles, current modeling predictions, and examples of pH sensors or proteins that have activities or ligand-binding affinities that are regulated by changes in intracellular pH.

https://www.physiology.org/doi/pdf/10.1152/physiol.00035.2006

Intracellular pH Sensors: Design Principles and Functional Significance

Over the past decade, there has been an explosion in the number of membrane transport proteins that have been shown to be sensitive to the abundance of phosphoinositides in the plasma membrane. These proteins include voltage-gated potassium and calcium channels, ion channels that mediate sensory and nociceptive responses, epithelial transport proteins and ionic exchangers. Each of the regulatory lipids is also under multifaceted regulatory control. Phosphoinositide modulation of membrane proteins in neurons often has a dramatic effect on neuronal excitability and synaptic transmitter release. The repertoire of lipid signalling mechanisms that regulate membrane proteins is intriguingly complex and provides a rich array of topics for neuroscience research.

Regulation of ion transport proteins by membrane phosphoinositides.

The discovery of the renal outer medullary K+ channel (ROMK, Kir1.1), the founding member of the inward-rectifying K+ channel (Kir) family, by Ho and Hebert in 1993 revolutionized our understanding of potassium channel biology and renal potassium handling. Because of the central role that ROMK plays in the regulation of salt and potassium homeostasis, considerable efforts have been invested in understanding the underlying molecular mechanisms. Here we provide a comprehensive guide to ROMK, spanning from the physiology in the kidney to the organization and regulation by intracellular factors to the structural basis of its function at the atomic level.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00181.2009

A comprehensive guide to the ROMK potassium channel: form and function in health and disease

The pH‐sensitive renal potassium channel Kir1.1 is important for K + homeostasis. Disruption of the pH‐sensing mechanism causes type II Bartter syndrome. The pH sensor is thought to be an anomalously titrated lysine residue (K80) that interacts with two arginine residues as part of an ‘RKR triad’. We show that a Kir1.1 orthologue from Fugu rubripes lacks this lysine and yet is still highly pH sensitive, indicating that K80 is not the H + sensor. Instead, K80 functionally interacts with A177 on transmembrane domain 2 at the ‘helix‐bundle crossing’ and controls the ability of pH‐dependent conformational changes to induce pore closure. Although not required for pH inhibition, K80 is indispensable for the coupling of pH gating to the extracellular K + concentration, explaining its conservation in most Kir1.1 orthologues. Furthermore, we demonstrate that instead of interacting with K80, the RKR arginine residues form highly conserved inter‐ and intra‐subunit interactions that are important for Kir channel gating and influence pH sensitivity indirectly.

/pdf/structural-and-functional-analysis-of-the-putative-ph-sensor-1tvfhsaoau.pdf

Katharine F Browne

Papers

Structural and functional analysis of the putative pH sensor in the Kir1.1 (ROMK) potassium channel