Inhibition of calcium-sensing receptors improves intestinal motility in obese mice through enteric neurons and vagal center

The calcium-sensing receptor (CaSR) is expressed in the gastrointestinal tract and plays a key role in regulating gastrointestinal functions, including motility. However, the effect of CaSR on the gastrointestinal motility of obese mice remains unclear. Our findings revealed that CaSR expression was elevated in the enteric nervous system (ENS) of high-fat diet (HFD)-induced obese mice, and its expression was reduced by the CaSR antagonist NPS-2143. While NPS-2143 had no significant effect on gastric emptying, it notably shortened intestinal transit time in obese mice. Mechanistically, NPS-2143 enhanced cholinergic and serotonergic signaling while inhibiting nitrergic and dopaminergic signaling in the ENS. Additionally, it increased c-fos-positive neurons in the nucleus tractus solitarius (NTS) and cholinergic neurons in the dorsal motor nucleus of the vagus (DMV). However, NPS-2143 also blocked voltage-dependent calcium channels, exerting a direct inhibitory effect on intestinal muscle strips ex vivo. These results suggest that inhibiting CaSR with NPS-2143 improves intestinal motility in obese mice, despite its direct inhibitory effect on intestinal strips. This improvement involves the participation of enteric neurons and vagal centers.