Smooth muscle cell mechanoelectrical feedback

Mechanical stimuli are critical for normal gastrointestinal function. Arthur Beyder, M.D., Ph.D. aims to understand how smooth muscle senses and responds to mechanical stimuli on the molecular level. In the smooth muscle cells, ion channels are involved in creating and coordinating electrical signals that lead to an influx of calcium, which is critical for contraction. In turn, gut wall stretch due to these contractions or distention from contents alters the ion channel function, leading to changes in contractions. When mechanical forces alter electrical activity, the process is called mechanoelectrical feedback.

Collaborating with Gianrico Farrugia, M.D., Dr. Beyder discovered through mechanoelectrical feedback that stretch significantly alters the function of voltage-gated sodium channels (NaV), specifically NaV1.5. Research shows that NaV1.5 is voltage- and mechanosensitive. The mechanisms of voltage-gating and mechanosensitivity in NaV1.5 are distinct and therefore pharmacologically targetable. This has also been verified through single-molecule biophysics. Therefore, the blockage of NaV1.5 mechanosensitivity significantly alters gastrointestinal motility. This study continues to pursue the process of mechanoelectrical feedback in the gastrointestinal tract using a variety of tools, ranging from conventional electrophysiology to optogenetics.

Enteroendocrine cell function

The gut is the largest endocrine organ in the human body. Enteroendocrine cells are hormone-producing cells that are sprinkled throughout the gut epithelium. In response to chemical and mechanical stimuli, these cells secrete a variety of important hormones, such as GLP-1 and GLP-2, PYY, CCK, and serotonin.

The enterochromaffin cell is a type of enteroendocrine cell that makes the vast majority of serotonin in the body. Serotonin is released by the enterochromaffin cell in response to chemical and mechanical stimuli. Understanding how mechanical forces lead to serotonin secretion in the enterochromaffin cell is the focus of this study.