title: Modulation of Kir4.2 rectification properties and pHi-sensitive run-down by association with Kir5.1.
abstract: Inwardly rectifying K+ channels (Kir) comprise seven subfamilies that can be subdivided further on the basis of cytosolic pH (pHi) sensitivity, rectification strength and kinetics, and resistance to run-down. Although distinct residues within each channel subunit define these properties, heteromeric association with other Kir subunits can modulate them. We identified such an effect in the wild-type forms of Kir4.2 and Kir5.1 and used this to further understand how the functional properties of Kir channels relate to their structures. Kir4.2 and a Kir4.2-Kir5.1 fusion protein were expressed in HEK293 cells. Inward currents from Kir4.2 were stable over 10 min and pHi-insensitive (pH 6 to 8). Conversely, currents from Kir4.2-Kir5.1 exhibited a pHi-sensitive run-down at slightly acidic pHi. At pHi 7.2, currents in response to voltage steps positive to EK were essentially time independent for Kir4.2 indicating rapid block by Mg2+. Coexpression with Kir5.1 significantly increased the blocking time constant, and increased steady-state outward current characteristic of weak rectifiers. Recovery from blockade at negative potentials was voltage dependent and 2 to 10 times slower in the homomeric channel. These results show that Kir5.1 converts Kir4.2 from a strong to a weak rectifier, rendering it sensitive to pHi, and suggesting that Kir5.1 plays a role in fine-tuning Kir4.2 activity.
authors.affiliation: Department of Medicine, Queen's University, Kingston, ON, Canada K7L 5G2.
authors.forename: Hung D
authors.initials: HD
authors.lastname: Lam
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lemay
authors.forename: M Martha
authors.initials: MM
authors.lastname: Briggs
authors.forename: Marco
authors.initials: M
authors.lastname: Yung
authors.forename: Ceredwyn E
authors.initials: CE
authors.lastname: Hill
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004594:Electrophysiology; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D051381:Rats; D013997:Time Factors; D000097062:Kir5.1 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D000097062:Kir5.1 Channel; C489469:Kir4.2 channel