Molecular and functional characterization of inwardly rectifying K+ currents in murine proximal colon

Abstract

Membrane potentials of gastrointestinal (GI) muscles are important because voltage dependent Ca²⁺ channels in smooth muscle cells (SMC) provide the Ca²⁺ that triggers contraction. Regulation of membrane potential is complicated because SMC are electrically coupled to interstitial cells of Cajal (ICC) and PDGFRα⁺ cells. Activation of conductances in any of these cells affects the excitability of the syncytium. We explored the role of inward rectifier K⁺ conductances in colonic ICC that might contribute to regulation of membrane potential. ICC expressed Kcnj2 (Kir2.1), Kcnj4 (Kir2.3), Kcnj14 (Kir2.4) and Kcnj5 (Kir3.4), Kcnj8 (Kir 6.1) and Kcnj11 (Kir6.2). Voltage clamp experiments showed activation of inward current when extracellular K⁺ ([K⁺]_o) was increased. The current was inwardly rectifying and inhibited by Ba²⁺ (10 μm) and ML-133 (10 μm). A similar current was not available in SMC. The current activated in ICC by elevated [K⁺]_o was not affect by tertiapinQ, and Gβγ, dialyzed into cells, failed to activate a unique, tertiapinQ-sensitive conductance. Freshly dispersed ICC showed no evidence of functional K_ATP. Pinacidil failed to activate current and the inward current activated by elevated [K⁺]_o was insensitive to glibenclamide. Under current clamp ML-133 caused depolarization of isolated ICC and of cells impaled with microelectrodes in intact muscle strips. These findings show that ICC, isolated freshly from colonic muscles, expressed a Ba²⁺-sensitive, inwardly rectifying K⁺ conductance. This conductance is due, most likely to the expression of multiple Kir2 family paralogues, and the inwardly rectifying conductance contributes to the regulation of resting potentials and excitability of colonic muscles.

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