Irritable bowel syndrome patients haveSCN5Achannelopathies that lead to decreased Na_V1.5 current and mechanosensitivity

Abstract

The SCN5A-encoded voltage-gated mechanosensitive Na channel Na1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. Na1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2-3% of patients have SCN5A missense mutations that alter Na1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting Na1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. Na1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated Na1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered Na1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in Na1.5 channels with abnormal voltage-dependent and mechanosensitive function. NEW & NOTEWORTHY The voltage-gated Na channel Na1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the Na1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant Na1.5 channels were loss of function in voltage dependence or mechanosensitivity.

Microbiota imprint gut–intrinsic neuronal programming and sympathetic activity

“…Our data also suggests that a particular population of gut–projecting vagal sensory neurons, enriched in transcript for the voltage gated sodium channel Nav1.5 , may play a role in mediating CNS–driven sympathetic suppression. It is intriguing to note that mutations in Nav1.5 have been described as a hallmark of a subset of irritable bowel syndrome (IBS) patients with constipation 48,49 . It is therefore plausible that for specific IBS cohorts, dysbiosis and changes in the local availability of SCFAs or additional microbial metabolites result in increased sympathetic activity, driving slower intestinal motility.…”

Voltage‐gated sodium channels: (NaV)igating the field to determine their contribution to visceral nociception

“…; Strege et al . ). Whether this is purely a consequence of reduced gastrointestinal contractility or whether Na V 1.5 channels also play a direct role in visceral sensation remains unclear, as Na V 1.5 mRNA transcripts are expressed in 18% of thoracolumbar and 51% of lumbosacral colon‐innervating DRG neurons (Hockley et al .…”

SCN5A mutation G615E results in NaV1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity

“…SCN5A mutations are well established to cause cardiac conduction disorders, called channelopathies. Interestingly, patients with SCN5A cardiac channelopathies have an increased prevalence of irritable bowel syndrome (IBS) [3], and conversely, functionally abnormal SCN5A mutations are present in 2-3% of IBS patients [4][5][6].…”