Extracellular Cl− regulates electrical slow waves and setting of smooth muscle membrane potential by interstitial cells of Cajal in mouse jejunum

Abstract

Intracellular Cl⁻ homeostasis is regulated by anion-permeable channels and transporters and contributes to excitability of many cell types including smooth muscle and interstitial cells of Cajal (ICC) . Our aims were to investigate the effects on electrical activity in mouse jejunal muscle strips, of substituting extracellular Cl⁻ (Cl⁻_o) with the impermeant anions, gluconate and isethionate. On reducing Cl⁻_o, effects were observed on electrical slow waves with small effects on smooth muscle membrane voltage (E_m). Restoration of Cl⁻ hyperpolarized smooth muscle E_m proportional to the change in Cl⁻_o concentration. Replacement of 90% of Cl⁻_o with gluconate reversibly abolished slow waves in 5/9 preparations. Slow waves were maintained in isethionate. Gluconate and isethionate substitution had similar concentration dependent effects on peak amplitude, frequency, width at half peak amplitude, rise time and decay time of residual slow waves. Gluconate reduced free ionized Ca²⁺ in Krebs solutions to 0.13 mm. In Krebs solutions containing normal Cl⁻ and 0.13 mm free Ca²⁺, slow wave frequency was lower, width at half peak amplitude was smaller and decay time was faster. The transient hyperpolarization following restoration of Cl⁻_o was not observed in W/W^v mice, which lack pacemaker ICC in the small intestine. We conclude that in smooth muscle cells, the resting Cl⁻ conductance is low, whereas transmembrane Cl⁻ movement in ICC plays a major role in generation or propagation of slow waves. Furthermore, these data support a role for ICC in setting smooth muscle E_m and that altering Cl⁻ homeostasis in ICC can alter smooth muscle E_m.

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