Na⁺/Ca²⁺ exchanger contributes to stool transport in mice with experimental diarrhea

Abstract

The Na+/Ca2+ exchanger (NCX) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na+ and Ca2+. To reveal the functional role of NCX on gastrointestinal motility, we have previously used NCX1 and NCX2 heterozygote knockout mice (HET). We found that NCX1 and NCX2 play important roles in the motility of the gastric fundus, ileum and distal colon. Therefore, we believed that NCX1 and NCX2 play an important role in transport of intestinal contents. Here, we investigated the role of NCX in a mouse model of drug-induced diarrhea. The fecal consistencies in NCX1 HET and NCX2 HET were assessed using a diarrhea induced by magnesium sulfate, 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2). NCX2 HET, but not NCX1 HET, exacerbated magnesium sulfate-induced diarrhea by increasing watery fecals. Likewise, 5-HT-induced diarrheas were exacerbated in NCX2 HET, but not NCX1 HET. However, NCX1 HET and NCX2 HET demonstrated PGE2 induced diarrhea similar to those of wild-type mice (WT). As well as the result of the distal colon shown previously, in the proximal and transverse colons of WT, the myenteric plexus layers and the longitudinal and circular muscle layers were strongly immunoreactive to NCX1 and NCX2. In this study, we demonstrate that NCX2 has important roles in development of diarrhea.

Stress decreases contraction of the colon, and the effects of stress are different among the regions of the colon

“…digestive system [1,13], and immune system [4,5]. Diarrhea and constipation are two of the most typical symptoms that appear with stress, and the colon is involved in these [10].…”

Roles of Na+/Ca2+exchanger 1 in digestive system physiology and pathophysiology

“…Although NCX1 and NCX2 were found to be expressed in the myenteric nerve plexus of the proximal colon and the colon transversum as well as longitudinal and annular muscular layers, the function of NCX1 and NCX2 in intermuscular neurons may be different from that in smooth muscle[74]. Kazuhiro et al have found that in a diarrhea model induced with magnesium sulfate or 5-HT, the diarrhea in NCX2 heterozygous knockout mice (NCX2 HET) was more serious than that in wild-type mice (WT), but the diarrhea in NCX1 heterozygous knockout mice (NCX1 HET) showed no significant changes from that of WT[75]. Magnesium sulfate-induced diarrhea was exacerbated in NCX2 HET by decreasing normal and soft fecal materials and increasing watery fecal materials, however, PGE2-induced diarrhea in NCX1 HET and NCX2 HET was similar to that in the WT[75].…”

“…Kazuhiro et al have found that in a diarrhea model induced with magnesium sulfate or 5-HT, the diarrhea in NCX2 heterozygous knockout mice (NCX2 HET) was more serious than that in wild-type mice (WT), but the diarrhea in NCX1 heterozygous knockout mice (NCX1 HET) showed no significant changes from that of WT[75]. Magnesium sulfate-induced diarrhea was exacerbated in NCX2 HET by decreasing normal and soft fecal materials and increasing watery fecal materials, however, PGE2-induced diarrhea in NCX1 HET and NCX2 HET was similar to that in the WT[75]. The researchers believe that this finding may be due to the mechanism of 5-HT-induced diarrhea involving stimulation of the 5-HT3 receptor in myenteric plexus neurons and its downstream cholinergic and tachykinin excitatory pathways[76,77].…”

Gastrointestinal motility modulation by stress is associated with reduced smooth muscle contraction through specific transient receptor potential channel

“…The stress response of the autonomic nervous system and endocrine system is indispensable for the maintenance of life, but when that stress becomes long-term or chronic, stress response can cause disability in social life. There are serious effects caused by stress, such as gastrointestinal disorders [ 32 ], depression [ 9 ], eating disorders [ 3 ], immunological disease [ 7 , 8 ], neurodegenerative disease [ 18 , 47 , 48 ], and cardiovascular diseases [ 11 ]. We now focus on the relationship between stress and gastrointestinal motility disorders among serious effects listed above.…”