Conditional deletion of IP3R1 by Islet1-Cre in mice reveals a critical role of IP3R1 in interstitial cells of Cajal in regulating GI motility.

Abstract

Background and aims: Inositol 1,4,5-trisphosphate receptor type 1 (IP₃R1) has been proposed to play a physiological role in regulating gastrointestinal (GI) motility, but the underlying cell-dependent mechanism remains unclear. Here, we utilized cell-specific IP₃R1 deletion strategies to address this question in mice.

Methods: Conditional IP₃R1 knockout mice using Wnt1-Cre, Islet1-Cre mice, and smMHC-Cre^EGFP were generated. Cell lineage tracing was performed to determine where gene deletion occurred in the GI tract. Whole-gut transit assay and isometric tension recording were used to assess GI function in vivo and in vitro.

Results: In the mouse GI tract, Islet1-Cre targeted smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs), but not enteric neurons. IP₃R1 deletion by Islet1-Cre (isR1KO) caused a phenotype of intestinal pseudo-obstruction (IPO), evidenced by prolonged whole-gut transit time, enlarged GI tract, abdominal distention, and early lethality. IP₃R1 deletion by Islet1-Cre not only reduced the frequency of spontaneous contractions but also decreased the contractile responses to the muscarinic agonist carbachol (CCh) and electrical field stimulation (EFS) in colonic circular muscles. By contrast, smMHC-Cre^EGFP only targeted SMCs in the mouse GI tract. Although IP₃R1 deletion by smMHC-Cre^EGFP (smR1KO) also reduced the contractile responses to CCh and EFS in colonic circular muscles, the frequency of spontaneous contractions was less affected, and neither global GI abnormalities nor early lethality was found in smR1KO mice.

Conclusions: IP₃R1 deletion in both ICCs and SMCs but not in SMCs alone causes an IPO phenotype, suggesting that IP₃R1 in ICCs plays an essential role in regulating GI motility in vivo.