Na+/Ca2+ exchanger 2-heterozygote knockout mice display decreased acetylcholine release and altered colonic motility in vivo

Background The Na+/Ca2+ exchanger (NCX) is a plasma membrane transporter involved in regulating intracellular Ca2+ concentrations. NCX is critical for Ca2+ regulation in cardiac muscle, vascular smooth muscle, and nerve fibers. However, little is known about the physiological role of NCX in the myenteric neurons and smooth muscles of the gastrointestinal tract. Methods To determine the role of NCX1 and NCX2 in gastrointestinal tissues, we examined electric field stimulation (EFS)-induced responses in the longitudinal smooth muscle of the distal colon in NCX1- and NCX2-heterozygote knockout mice. Key Results We found that the amplitudes of EFS-induced relaxation that persisted during EFS were greater in NCX2 heterozygous mice (HET) than in wild-type mice (WT). Under the nonadrenergic, noncholinergic (NANC) condition, EFS-induced relaxation in NCX2 HET was similar in amplitude to that of WT. In addition, an NCX inhibitor, YM-244769 enhanced EFS-induced relaxation but did not affect EFS-induced relaxation under the NANC condition, as in NCX2 HET. Unlike NCX2 HET, NCX1 HET displayed no marked changes in colonic motility. These results indicate that cholinergic function in the colon is altered in NCX2 HET. The magnitude of acetylcholine (ACh)-induced contraction in NCX2 HET was similar to that in WT. In contrast, EFS-induced ACh release was reduced in NCX2 HET compared with that in WT. Conclusions & Inferences In this study, we demonstrate that NCX2 regulates colonic motility by altering ACh release onto the myenteric neurons of the distal colon.