Role of ion channel mechanosensitivity in the gut: Mechano-electrical feedback exemplified by stretch-dependence of Na_v1.5

Na_V1.5 is a voltage-gated sodium channel found in the human gastrointestinal tract. In smooth muscle cells (SMC) and interstitial cells of Cajal (ICC), Na_V1.5 regulates the resting potential as well as slow wave upstroke and frequency. Mutations in SCN5A, the gene coding for Na_V1.5, are associated with gastrointestinal functional disorders. Some patients with irritable bowel syndrome (IBS) have SCN5A mutations that result in functionally abnormal channels. Na_V1.5 is mechanosensitive, and some of the mutations associated with gastrointestinal (GI) motility disorders have impaired mechanosensitivity. Na_V1.5 mechanosensitivity involves the actin cytoskeleton and associating proteins as well as the lipid bilayer. Mechanical stimulation of Na_V1.5 results in an increase in peak current, acceleration of the voltage-dependent activation & inactivation and slowed recovery from inactivation. Biophysical modeling is increasingly used as a tool for investigating the effect of Na_V1.5 and other mechanosensitive components in slow wave generation. We summarize the existing models of gastrointestinal cellular electrical activity, and specifically a model of Na_V1.5 mechanosensitivity that has been incorporated into one of the cell models. In agreement with the experimental data, mechanical stimulation of Na_V1.5 results in increased excitability of the cell model in silico. In this chapter we discuss the current knowledge of the molecular mechanism of Na_V1.5 mechanosensitivity, mechano-electrical consequences of Na_V1.5 stretch in cells and propose physiologic and pathophysiologic consequences.