title: Quantification of gastrointestinal sodium channelopathy.
abstract: Na(v)1.5 sodium channels, encoded by SCN5A, have been identified in human gastrointestinal interstitial cells of Cajal (ICC) and smooth muscle cells (SMC). A recent study found a novel, rare missense R76C mutation of the sodium channel interacting protein telethonin in a patient with primary intestinal pseudo-obstruction. The presence of a mutation in a patient with a motility disorder, however, does not automatically imply a cause-effect relationship between the two. Patch clamp experiments on HEK-293 cells previously established that the R76C mutation altered Na(v)1.5 channel function. Here the process through which these data were quantified to create stationary Markov state models of wild-type and R76C channel function is described. The resulting channel descriptions were included in whole cell ICC and SMC computational models and simulations were performed to assess the cellular effects of the R76C mutation. The simulated ICC slow wave was decreased in duration and the resting membrane potential in the SMC was depolarized. Thus, the R76C mutation was sufficient to alter ICC and SMC cell electrophysiology. However, the cause-effect relationship between R76C and intestinal pseudo-obstruction remains an open question.
authors.affiliation: Division of Bioengineering, National University of Singapore, 9 Engineering Drive 1, Block EA #03-12 Singapore 117576, Singapore. yc@nus.edu.sg
authors.forename: Yong Cheng
authors.initials: YC
authors.lastname: Poh
authors.forename: Arthur
authors.initials: A
authors.lastname: Beyder
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strege
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
authors.forename: Martin L
authors.initials: ML
authors.lastname: Buist
mesh_terms: D053447:Channelopathies / Q000235:genetics* / Q000503:physiopathology; D057809:HEK293 Cells; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics* / Q000503:physiopathology; D007583:Jejunum / Q000166:cytology / Q000378:metabolism; D008390:Markov Chains; D008564:Membrane Potentials / Q000502:physiology; D008957:Models, Genetic; D009130:Muscle, Smooth / Q000503:physiopathology; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels